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References_end </body> </html> </notes> <label text="BCL3/HDAC1"/> <bbox w="100.0" h="120.0" x="4180.0" y="2200.0"/> <glyph class="macromolecule" id="s70_sa47"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HDAC1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="HDAC1"/> <bbox w="80.0" h="40.0" x="4193.5" y="2256.0"/> </glyph> <glyph class="macromolecule" id="s71_sa48"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:BCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="4190.5" y="2212.0"/> </glyph> </glyph> <glyph class="complex" id="s202_csa23" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:BCL3:NFKB1_p50* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: p50/p50/BCL3 PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="NFkB p50/p50/BCL3"/> <bbox w="103.5" h="144.5" x="4048.25" y="2167.75"/> <glyph class="macromolecule" id="s201_sa157"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:BCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="4060.0" y="2250.0"/> </glyph> <glyph class="macromolecule multimer" id="s607_sa531"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. 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xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCOR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="NCOR1"/> <bbox w="80.0" h="40.0" x="3710.0" y="2770.0"/> </glyph> <glyph class="macromolecule" id="s476_sa401"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HDAC3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="HDAC3"/> <bbox w="80.0" h="40.0" x="3705.0" y="2716.5"/> </glyph> </glyph> <glyph class="complex" id="s490_csa39" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NCOR1:PPARG:SUMO*:TBL1X:TBL1XR1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="s483"/> <bbox w="195.0" h="170.0" x="3812.5" y="2825.0"/> <glyph class="macromolecule" id="s491_sa411"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TBL1X Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="TBL1X"/> <bbox w="80.0" h="40.0" x="3827.5" y="2835.0"/> </glyph> <glyph class="macromolecule" id="s493_sa413"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NCOR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="NCOR1"/> <bbox w="80.0" h="40.0" x="3917.5" y="2875.0"/> </glyph> <glyph class="macromolecule" id="s494_sa414"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TBL1XR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="TBL1XR1"/> <bbox w="80.0" h="40.0" x="3827.5" y="2875.0"/> </glyph> <glyph class="macromolecule" id="s495_sa415"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4. References_end </body> </html> </notes> <label text="PPARG"/> <bbox w="80.0" h="40.0" x="3832.5" y="2925.0"/> </glyph> <glyph class="macromolecule" id="s496_sa416"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SUMO1 HUGO:SUMO2 HUGO:SUMO3 HUGO:SUMO4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <label text="SUMO*"/> <bbox w="80.0" h="40.0" x="3912.5" y="2925.0"/> </glyph> <glyph class="macromolecule" id="s1378_sa1066"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:HDAC3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="HDAC3"/> <bbox w="80.0" h="40.0" x="3920.0" y="2830.0"/> </glyph> </glyph> <glyph class="complex" id="s540_csa41" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IRF4:MIR125B1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:16243976 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 ion resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR References_end </body> </html> </notes> <label text="IRF4/MIR125B1"/> <bbox w="100.0" h="120.0" x="2170.0" y="2463.5"/> <glyph class="nucleic acid feature" id="s541_sa461"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRF4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20729857 KDM6B ( Jmjd3) demethylates promoter region of IRF4 and upregulates its expression References_end </body> </html> </notes> <label text="IRF4"/> <bbox w="90.0" h="25.0" x="2175.0" y="2481.0"/> <glyph class="unit of information" id="_900d7cae-9108-48f0-8b8f-cbfad4497cdb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2210.0" y="2476.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s542_sa462"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR125B1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16243976 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 ion resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR References_end </body> </html> </notes> <label text="MIR125B1"/> <bbox w="90.0" h="25.0" x="2175.0" y="2511.0"/> <glyph class="unit of information" id="_91ae750b-c441-4226-ba09-30cb9aeb26f7"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2205.0" y="2506.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s599_csa44"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:VEGFA:VEGFR1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="s599"/> <bbox w="100.0" h="120.0" x="1660.0" y="4200.0"/> <glyph class="macromolecule" id="s602_sa523"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21765015, PMID:22869907 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production. CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. specific inhibition of PHD3 increases VEGF production. References_end </body> </html> </notes> <label text="trVEGFR1*"/> <bbox w="80.0" h="40.0" x="1670.0" y="4210.0"/> <glyph class="unit of information" id="_737669a8-6be7-4fbb-a58f-96e8ee66accd"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1685.0" y="4205.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s600_sa524"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:VEGFA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="80.0" h="40.0" x="1670.0" y="4265.0"/> </glyph> </glyph> <glyph class="complex" id="s620_csa28" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL13:IL13RA1:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620, PMID:12223527, PMID:20510870 JAK1 associated with IL4R and JAK2 or TYK associated with IL13RA1 participate in signal transduction; They phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain. PMID:23124025 IL13 signaling aktivates JAK2 and TYK2 not JAK1. References_end </body> </html> </notes> <label text="IL13/Receptor-TYPE_2"/> <bbox w="290.5" h="170.0" x="354.75" y="2885.0"/> <glyph class="macromolecule" id="s315_sa248"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="545.25" y="2985.0"/> <glyph class="state variable" id="_e73857ec-e355-469f-8433-321f700901a8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="537.75" y="3000.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s316_sa249"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TYK2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODUULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="545.25" y="2945.0"/> <glyph class="state variable" id="_6e4c7c17-f339-4738-94bf-64ef203c8173"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="537.75" y="2960.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s339_sa268"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="445.25" y="2910.0"/> <glyph class="state variable" id="_c33d2a90-332a-485d-978e-412ddd1f425d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="517.75" y="2944.3892"/> </glyph> <glyph class="unit of information" id="_d51bf4da-8b6d-4f7d-8236-98c7577ff905"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="462.75" y="2905.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s340_sa269"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="80.0" h="50.0" x="445.25" y="2960.0"/> <glyph class="state variable" id="_13488311-cde1-444d-964d-245fc7ff8131"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="517.75" y="2993.7566"/> </glyph> <glyph class="unit of information" id="_8c64f81f-6f30-492d-873a-a4162fa0cf9c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="462.75" y="2955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s337_sa270"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. References_end </body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="365.25" y="2935.0"/> </glyph> <glyph class="macromolecule" id="s386_sa309"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="545.25" y="2905.0"/> <glyph class="state variable" id="_556cb561-90e0-4257-b1bb-9ae76e1113ab"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="540.25" y="2920.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s626_csa26" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL13:IL13RA2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 References_end </body> </html> </notes> <label text="IL13/IL13RA2"/> <bbox w="100.0" h="120.0" x="730.0" y="3150.0"/> <glyph class="macromolecule" id="s313_sa245"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175 IL13 signaling via IL13RA2 induces TGFB production in MDSC. References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="80.0" h="50.0" x="739.64703" y="3202.1177"/> <glyph class="unit of information" id="_328c24e8-013d-41e9-b805-65b02498a2c1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="757.14703" y="3197.1177"/> </glyph> </glyph> <glyph class="macromolecule" id="s314_sa246"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. References_end </body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="738.64703" y="3159.1177"/> </glyph> </glyph> <glyph class="complex" id="s632_csa31" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IP3:IP3R* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="IP3:IP3R*"/> <bbox w="86.0" h="115.0" x="1754.75" y="2883.5"/> <glyph class="macromolecule" id="s404_sa334"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITPR1 HUGO:ITPR2 HUGO:ITPR3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="IP3R*"/> <bbox w="80.0" h="50.0" x="1756.875" y="2929.0"/> <glyph class="unit of information" id="_c08abcaf-c8ad-44c8-95cb-532b4b8f17cf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1774.375" y="2924.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s403_sa335"> <label text="IP3"/> <bbox w="70.0" h="25.0" x="1761.875" y="2905.0"/> </glyph> </glyph> <glyph class="complex" id="s633_csa32" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IRS2:PLCG1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="IRS2:PLCG1"/> <bbox w="100.0" h="120.0" x="1441.0" y="2731.0"/> <glyph class="macromolecule" id="s416_sa342"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="IRS2"/> <bbox w="80.0" h="40.0" x="1452.5" y="2743.0"/> <glyph class="state variable" id="_3f9d0e57-259e-40ae-a35a-58da06ae6efe"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1445.0" y="2758.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s415_sa343"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="1451.0" y="2781.0"/> <glyph class="state variable" id="_69247765-70e1-4bc5-afa2-a13cd9468051"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1443.5" y="2796.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s791_csa57" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TNF:TNFR2*:TRAF1:TRAF2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors.TNFR2 interacts with TRAF2 and TRAF1. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TNFR2"/> <bbox w="190.0" h="120.0" x="5915.0" y="2430.0"/> <glyph class="macromolecule" id="s795_sa707"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, PMID:14625680 TNF and IFNG cooperate in the activation of macrophages. References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="6010.0" y="2440.0"/> </glyph> <glyph class="macromolecule" id="s794_sa706"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="5925.0" y="2480.0"/> <glyph class="state variable" id="_88a28e17-b153-4e21-a32a-d22f23fc64d3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6000.0" y="2493.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s793_sa705"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNFR2 interacts with TRAF2 and TRAF1. References_end </body> </html> </notes> <label text="TRAF1"/> <bbox w="80.0" h="40.0" x="5925.0" y="2440.0"/> </glyph> <glyph class="macromolecule" id="s792_sa704"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFRSF1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR2*"/> <bbox w="80.0" h="50.0" x="6015.0" y="2485.0"/> <glyph class="unit of information" id="_54673327-5384-403e-ab41-0a8e1641b915"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6032.5" y="2480.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s877_csa64" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD11*:CD18* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:20404138 Inhibition of Mac-1 (CD11b/CD18) reduces myeloid cell recruitment References_end </body> </html> </notes> <label text="s877"/> <bbox w="110.0" h="160.0" x="4415.0" y="3790.0"/> <glyph class="macromolecule" id="s879_sa779"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotoxicity. PMID:1679046 INFG apregulates CD18 surface expression. Inhibition of CD18 inhibits monocyte binding to tumor target cells and tumoricidal activity. References_end </body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="4430.0" y="3855.0"/> <glyph class="unit of information" id="_665ece6e-96c0-46b8-b1ad-1e812c3f7b1e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4447.5" y="3850.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s887_sa786"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:ITGAX HUGO:ITGAM HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:1679046 Probably all CD11 proteins (a,b,c) participates in macrophage tumoricidal activity. References_end </body> </html> </notes> <label text="CD11*"/> <bbox w="80.0" h="50.0" x="4430.0" y="3805.0"/> <glyph class="unit of information" id="_322c5521-03b0-4817-ba27-134f183377c1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4447.5" y="3800.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s978_csa70" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PKA*:PKA_R* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="s978"/> <bbox w="100.0" h="140.0" x="1910.0" y="3075.0"/> <glyph class="macromolecule" id="s981_sa327"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKACA HGNC:9380 ENTREZ:5566 UNIPROT:P17612 GENECARDS:PRKACA HUGO:PRKACB HGNC:9381 ENTREZ:5567 UNIPROT:P22694 GENECARDS:PRKACB HUGO:PRKACG HGNC:9382 ENTREZ:5568 UNIPROT:P22612 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:57845 KEGG:5566 ATLASONC:GC_PRKACA WIKI:PRKACA REACTOME:57847 KEGG:5567 ATLASONC:GC_PRKACB WIKI:PRKACB PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway PMID:10925299 IL13 activates Arginase activity downstream of cAMP/PKA References_end </body> </html> </notes> <label text="PKA*"/> <bbox w="80.0" h="40.0" x="1920.0" y="3145.0"/> </glyph> <glyph class="macromolecule" id="s979_sa884"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKAB1 HGNC:9378 ENTREZ:5564 UNIPROT:Q9Y478 GENECARDS:PRKAB1 REACTOME:49384 KEGG:5564 ATLASONC:PRKAB1ID44100ch12q24 WIKI:PRKAB1 HUGO:PRKAB2 HGNC:9379 ENTREZ:5565 UNIPROT:O43741 GENECARDS:PRKAB2 REACTOME:49386 ATLASONC:GC_PRKAB2 WIKI:PRKAB2 HUGO:PRKAG1 HGNC:9385 ENTREZ:5571 UNIPROT:P54619 GENECARDS:PRKAG1 REACTOME:49388 KEGG:5571 ATLASONC:GC_PRKAG1 WIKI:PRKAG1 HUGO:PRKAG2 HGNC:9386 ENTREZ:51422 UNIPROT:Q9UGJ0 GENECARDS:PRKAG2 REACTOME:49390 KEGG:51422 ATLASONC:GC_PRKAG2 WIKI:PRKAG2 HUGO:PRKAG3 HGNC:9387 ENTREZ:53632 UNIPROT:Q9UGI9 GENECARDS:PRKAG3 REACTOME:49392 KEGG:53632 ATLASONC:GC_PRKAG3 WIKI:PRKAG3 HUGO:PRKAR1A HGNC:9388 ENTREZ:5573 UNIPROT:P10644 GENECARDS:PRKAR1A REACTOME:57837 KEGG:5573 ATLASONC:PRKAR1AID387 WIKI:PRKAR1A HUGO:PRKAR1B HGNC:9390 ENTREZ:5575 UNIPROT:P31321 GENECARDS:PRKAR1B REACTOME:57839 KEGG:5575 ATLASONC:GC_PRKAR1B WIKI:PRKAR1B HUGO:PRKAR2A HGNC:9391 ENTREZ:5576 UNIPROT:P13861 GENECARDS:PRKAR2A REACTOME:57841 KEGG:5576 ATLASONC:GC_PRKAR2A WIKI:PRKAR2A HUGO:PRKAR2B HGNC:9392 ENTREZ:5577 UNIPROT:P31323 GENECARDS:PRKAR2B REACTOME:57843 KEGG:5577 ATLASONC:GC_PRKAR2B WIKI:PRKAR2B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway References_end </body> </html> </notes> <label text="PKA_R*"/> <bbox w="80.0" h="40.0" x="1920.0" y="3095.0"/> </glyph> </glyph> <glyph class="complex" id="s983_csa72" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PKA*:PKA_R*:cAMP Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="s978"/> <bbox w="100.0" h="170.0" x="2110.0" y="2990.0"/> <glyph class="simple chemical" id="s986_sa885"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. </body> </html> </notes> <label text="cAMP"/> <bbox w="70.0" h="25.0" x="2125.0" y="2997.5"/> </glyph> <glyph class="macromolecule" id="s984_sa886"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKAB1 HGNC:9378 ENTREZ:5564 UNIPROT:Q9Y478 GENECARDS:PRKAB1 REACTOME:49384 KEGG:5564 ATLASONC:PRKAB1ID44100ch12q24 WIKI:PRKAB1 HUGO:PRKAB2 HGNC:9379 ENTREZ:5565 UNIPROT:O43741 GENECARDS:PRKAB2 REACTOME:49386 ATLASONC:GC_PRKAB2 WIKI:PRKAB2 HUGO:PRKAG1 HGNC:9385 ENTREZ:5571 UNIPROT:P54619 GENECARDS:PRKAG1 REACTOME:49388 KEGG:5571 ATLASONC:GC_PRKAG1 WIKI:PRKAG1 HUGO:PRKAG2 HGNC:9386 ENTREZ:51422 UNIPROT:Q9UGJ0 GENECARDS:PRKAG2 REACTOME:49390 KEGG:51422 ATLASONC:GC_PRKAG2 WIKI:PRKAG2 HUGO:PRKAG3 HGNC:9387 ENTREZ:53632 UNIPROT:Q9UGI9 GENECARDS:PRKAG3 REACTOME:49392 KEGG:53632 ATLASONC:GC_PRKAG3 WIKI:PRKAG3 HUGO:PRKAR1A HGNC:9388 ENTREZ:5573 UNIPROT:P10644 GENECARDS:PRKAR1A REACTOME:57837 KEGG:5573 ATLASONC:PRKAR1AID387 WIKI:PRKAR1A HUGO:PRKAR1B HGNC:9390 ENTREZ:5575 UNIPROT:P31321 GENECARDS:PRKAR1B REACTOME:57839 KEGG:5575 ATLASONC:GC_PRKAR1B WIKI:PRKAR1B HUGO:PRKAR2A HGNC:9391 ENTREZ:5576 UNIPROT:P13861 GENECARDS:PRKAR2A REACTOME:57841 KEGG:5576 ATLASONC:GC_PRKAR2A WIKI:PRKAR2A HUGO:PRKAR2B HGNC:9392 ENTREZ:5577 UNIPROT:P31323 GENECARDS:PRKAR2B REACTOME:57843 KEGG:5577 ATLASONC:GC_PRKAR2B WIKI:PRKAR2B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway References_end </body> </html> </notes> <label text="PKA_R*"/> <bbox w="80.0" h="40.0" x="2120.0" y="3040.0"/> </glyph> <glyph class="macromolecule" id="s985_sa887"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKACA HGNC:9380 ENTREZ:5566 UNIPROT:P17612 GENECARDS:PRKACA HUGO:PRKACB HGNC:9381 ENTREZ:5567 UNIPROT:P22694 GENECARDS:PRKACB HUGO:PRKACG HGNC:9382 ENTREZ:5568 UNIPROT:P22612 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:57845 KEGG:5566 ATLASONC:GC_PRKACA WIKI:PRKACA REACTOME:57847 KEGG:5567 ATLASONC:GC_PRKACB WIKI:PRKACB PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway PMID:10925299 IL13 activates Arginase activity downstream of cAMP/PKA References_end </body> </html> </notes> <label text="PKA*"/> <bbox w="80.0" h="40.0" x="2120.0" y="3090.0"/> </glyph> </glyph> <glyph class="complex" id="s987_csa73" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PKA_R*:cAMP Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="s978"/> <bbox w="105.0" h="119.0" x="2247.5" y="2915.5"/> <glyph class="simple chemical" id="s988_sa888"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. </body> </html> </notes> <label text="cAMP"/> <bbox w="70.0" h="25.0" x="2265.0" y="2932.5"/> </glyph> <glyph class="macromolecule" id="s989_sa889"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PRKAB1 HGNC:9378 ENTREZ:5564 UNIPROT:Q9Y478 GENECARDS:PRKAB1 REACTOME:49384 KEGG:5564 ATLASONC:PRKAB1ID44100ch12q24 WIKI:PRKAB1 HUGO:PRKAB2 HGNC:9379 ENTREZ:5565 UNIPROT:O43741 GENECARDS:PRKAB2 REACTOME:49386 ATLASONC:GC_PRKAB2 WIKI:PRKAB2 HUGO:PRKAG1 HGNC:9385 ENTREZ:5571 UNIPROT:P54619 GENECARDS:PRKAG1 REACTOME:49388 KEGG:5571 ATLASONC:GC_PRKAG1 WIKI:PRKAG1 HUGO:PRKAG2 HGNC:9386 ENTREZ:51422 UNIPROT:Q9UGJ0 GENECARDS:PRKAG2 REACTOME:49390 KEGG:51422 ATLASONC:GC_PRKAG2 WIKI:PRKAG2 HUGO:PRKAG3 HGNC:9387 ENTREZ:53632 UNIPROT:Q9UGI9 GENECARDS:PRKAG3 REACTOME:49392 KEGG:53632 ATLASONC:GC_PRKAG3 WIKI:PRKAG3 HUGO:PRKAR1A HGNC:9388 ENTREZ:5573 UNIPROT:P10644 GENECARDS:PRKAR1A REACTOME:57837 KEGG:5573 ATLASONC:PRKAR1AID387 WIKI:PRKAR1A HUGO:PRKAR1B HGNC:9390 ENTREZ:5575 UNIPROT:P31321 GENECARDS:PRKAR1B REACTOME:57839 KEGG:5575 ATLASONC:GC_PRKAR1B WIKI:PRKAR1B HUGO:PRKAR2A HGNC:9391 ENTREZ:5576 UNIPROT:P13861 GENECARDS:PRKAR2A REACTOME:57841 KEGG:5576 ATLASONC:GC_PRKAR2A WIKI:PRKAR2A HUGO:PRKAR2B HGNC:9392 ENTREZ:5577 UNIPROT:P31323 GENECARDS:PRKAR2B REACTOME:57843 KEGG:5577 ATLASONC:GC_PRKAR2B WIKI:PRKAR2B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18501881, PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway References_end </body> </html> </notes> <label text="PKA_R*"/> <bbox w="80.0" h="40.0" x="2260.0" y="2965.0"/> </glyph> </glyph> <glyph class="source and sink" id="s543_sa463" compartmentRef="c8_ca8"> <label text="s543"/> <bbox w="30.0" h="30.0" x="2075.0" y="2510.0"/> </glyph> <glyph class="source and sink" id="s601_sa525"> <label text="s601"/> <bbox w="30.0" h="30.0" x="1815.0" y="4245.0"/> </glyph> <glyph class="nucleic acid feature" id="s26_sa22" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:1431106 TNF is ploinfammatory cytokine induced tumoricidal activity of macrophages PMID:10754326 Human TNF-alpha gene has binding sites for NF-kappa B. By transient transfection, NF-kappa B p65 and p50 synergistically activated the TNF-alpha promoter. Although both the kappa B1 and kappa B3 sites bound transcriptionally active NF-kappa B p50/p65 heterodimers, only the kappa B1 site contributed to down-regulation by NF-kappa B p50 homodimers. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC References_end </body> </html> </notes> <label text="TNF"/> <bbox w="105.0" h="57.5" x="3965.0" y="2470.0"/> </glyph> <glyph class="nucleic acid feature" id="s75_sa52" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL1A"/> <bbox w="70.0" h="25.0" x="4805.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s76_sa53" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1B. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="70.0" h="25.0" x="4895.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s108_sa81" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="70.0" h="25.0" x="4532.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s109_sa82" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:9743347 IL-13 blocks NF-κB-dependent production of IL6 PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC References_end </body> </html> </notes> <label text="IL6"/> <bbox w="70.0" h="25.0" x="4441.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s110_sa83" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator. References_end </body> </html> </notes> <label text="IL12p40*"/> <bbox w="70.0" h="25.0" x="4622.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s135_sa107" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HMOX1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. References_end </body> </html> </notes> <label text="HMOX1"/> <bbox w="70.0" h="25.0" x="3883.0" y="2137.5"/> </glyph> <glyph class="nucleic acid feature" id="s138_sa110" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NOS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:17476345 NOS2, a heme-containing enzyme that catalyzes the synthesis of NO and citrulline from l‐Arg, is expressed by various cells of the immune system, and its activa- tion is considered a hallmark of classically activated macrophages (also known as M1 macrophages), a macrophage subset that pro- duces proinflammatory cytokines and acts as the effector cell in the killing of invading pathogens and tumor cells. PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses NF-kB dependent expression NOS2, Ccl3, Ccl7, Cxcl10 PMID:17689680 STAT1 binds to INOS promoter and induces INOS expression and NO production downstream of IFNG in murine macrophages. Acetylation inhibits STAT1 binding to promotor. PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID: 16424049 iNOS expression was induced by IFN-gamma stimulation in MDSC, probably via STAT1. References_end </body> </html> </notes> <label text="NOS2"/> <bbox w="113.0" h="67.5" x="3797.0" y="3035.0"/> </glyph> <glyph class="nucleic acid feature" id="s144_sa116" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP9 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="70.0" h="25.0" x="2055.0" y="3317.5"/> </glyph> <glyph class="nucleic acid feature" id="s145_sa117" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ARG1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:12193690 Up-regulation of IL4RA by IL10 correlates with increased IL4-dependent expression of arginase-1 (ARG1). PMID: PMID:21670502 KLF4 together with STAT6 upregulates expression of PPARG and ARG1 downstream of IL4 in macrophages. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID: 20644162 Human MDSC express AGR1 PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. References_end </body> </html> </notes> <label text="ARG1"/> <bbox w="116.0" h="58.5" x="2525.75" y="3009.5"/> </glyph> <glyph class="nucleic acid feature" id="s146_sa118" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ARG2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces ARG2 (arginase-2) expression References_end </body> </html> </notes> <label text="ARG2"/> <bbox w="113.0" h="60.5" x="2673.75" y="3009.5"/> </glyph> <glyph class="nucleic acid feature" id="s156_sa128" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="CSF3"/> <bbox w="70.0" h="25.0" x="4988.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s216_sa200" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="IL18"/> <bbox w="70.0" h="25.0" x="5080.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s219_sa203" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="70.0" h="25.0" x="4715.5" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s318_sa251" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. PMID:21372296 HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). References_end </body> </html> </notes> <label text="TGFB1"/> <bbox w="132.0" h="54.0" x="2789.0" y="2613.0"/> </glyph> <glyph class="nucleic acid feature" id="s320_sa253" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL13RA2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 Other receptor of IL13 is IL13RA2 References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="70.0" h="25.0" x="1025.0" y="2922.5"/> </glyph> <glyph class="nucleic acid feature" id="s391_sa323" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ABCB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="ABCB1"/> <bbox w="70.0" h="25.0" x="4170.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s417_sa344" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID: PMID:2422040 MHC II provides antigen presentation by human monocytes. PMID:16243976 INFG upregulates surface expression of MHC II. IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 resulted in increased surface expression of MHC II. PMID:15644117 HMGB1 upregulates the expression of MHC class II molecules on the surface of macrophages. References_end </body> </html> </notes> <label text="MHC class II*"/> <bbox w="70.0" h="25.0" x="5195.0" y="2931.0"/> </glyph> <glyph class="nucleic acid feature" id="s441_sa368" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAOA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:23124025 IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6 IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6. References_end </body> </html> </notes> <label text="MAOA"/> <bbox w="70.0" h="25.0" x="2905.0" y="3529.0"/> </glyph> <glyph class="nucleic acid feature" id="s450_sa377" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TIMP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23124025 IL4 induces expression of TIMP3 via JAK1 pathway References_end </body> </html> </notes> <label text="TIMP3"/> <bbox w="70.0" h="25.0" x="1365.0" y="2455.5"/> </glyph> <glyph class="nucleic acid feature" id="s464_sa392" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="70.0" h="25.0" x="4292.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s467_sa395" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="70.0" h="25.0" x="4390.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s498_sa418" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL7 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <label text="CCL7"/> <bbox w="70.0" h="25.0" x="4515.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s499_sa419" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="70.0" h="25.0" x="4615.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s510_sa430" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461, PMID:19567879 IL4 induces expression of IRF4 probably via STAT6/KDM6B ( Jmjd3) pathway. PMID:20729857 KDM6B ( Jmjd3) demethylates promoter region of IRF4 and upregulates its expression References_end </body> </html> </notes> <label text="IRF4"/> <bbox w="70.0" h="25.0" x="2373.5" y="2501.0"/> </glyph> <glyph class="nucleic acid feature" id="s513_sa434" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CIITA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:20580461 The expression of Ciita, the gene encoding the MHC class II transactivator C2ta, was dependent on Irf4, both in the steady state, as well as for the efficient induction by IL-4. PMID:12928384 GM-CSF increases types I and III CIITA mRNA in primary human monocytes, while IFNG increases types III and IV CIITA transcripts References_end </body> </html> </notes> <label text="CIITA"/> <bbox w="70.0" h="25.0" x="5286.0" y="2852.5"/> </glyph> <glyph class="nucleic acid feature" id="s518_sa440" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CYP1B1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="CYP1B1"/> <bbox w="70.0" h="25.0" x="2211.0" y="2682.0"/> </glyph> <glyph class="nucleic acid feature" id="s520_sa442" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL24 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="CCL24"/> <bbox w="70.0" h="25.0" x="2311.0" y="2682.0"/> </glyph> <glyph class="nucleic acid feature" id="s522_sa444" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MPP6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="MPP6"/> <bbox w="70.0" h="25.0" x="2421.0" y="2682.0"/> </glyph> <glyph class="nucleic acid feature" id="s524_sa446" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1RN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 References_end </body> </html> </notes> <label text="IL1RN"/> <bbox w="70.0" h="25.0" x="2521.0" y="2686.0"/> </glyph> <glyph class="nucleic acid feature" id="s566_sa488" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:VEGFA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21372296 HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="70.0" h="25.0" x="1925.0" y="3317.5"/> </glyph> <glyph class="nucleic acid feature" id="s597_sa521" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21765015, PMID:22869907 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production. CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. specific inhibition of PHD3 increases VEGF production. References_end </body> </html> </notes> <label text="VEGFR1*"/> <bbox w="70.0" h="25.0" x="4210.0" y="3019.0"/> </glyph> <glyph class="nucleic acid feature" id="s447_sa374" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:DUSP1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16184516 In silico analysis identified a STAT6 binding site at position +99 (relative to the transcriptional start site) of the mouse DUSP1 promoter. References_end </body> </html> </notes> <label text="DUSP1"/> <bbox w="70.0" h="25.0" x="1267.5" y="2451.0"/> </glyph> <glyph class="nucleic acid feature" id="s684_sa608" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine CCL4 (MIP1B). References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="70.0" h="25.0" x="4725.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s700_sa626" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine CCL4 (MIP1B). References_end </body> </html> </notes> <label text="CLL4"/> <bbox w="70.0" h="25.0" x="4825.0" y="2731.0"/> </glyph> <glyph class="nucleic acid feature" id="s737_sa663" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD86 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. References_end </body> </html> </notes> <label text="CD86"/> <bbox w="70.0" h="25.0" x="5475.0" y="2747.5"/> </glyph> <glyph class="nucleic acid feature" id="s738_sa664" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD80 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. References_end </body> </html> </notes> <label text="CD80"/> <bbox w="70.0" h="25.0" x="5435.0" y="2797.5"/> </glyph> <glyph class="nucleic acid feature" id="s739_sa665" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD40 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. References_end </body> </html> </notes> <label text="CD40"/> <bbox w="70.0" h="25.0" x="5395.0" y="2847.5"/> </glyph> <glyph class="nucleic acid feature" id="s769_sa688" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="JUN"/> <bbox w="70.0" h="25.0" x="3200.0" y="2356.0"/> </glyph> <glyph class="nucleic acid feature" id="s849_sa748" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL23A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL23A"/> <bbox w="70.0" h="25.0" x="5168.0" y="2476.0"/> </glyph> <glyph class="nucleic acid feature" id="s869_sa770" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. References_end </body> </html> </notes> <label text="STAB1"/> <bbox w="70.0" h="25.0" x="1205.0" y="3277.5"/> </glyph> <glyph class="nucleic acid feature" id="s872_sa773" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="FCER2"/> <bbox w="70.0" h="25.0" x="1295.0" y="3277.5"/> </glyph> <glyph class="nucleic acid feature" id="s920_sa821" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD209 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expresion of CD209 downstream of IL4, probably via STAT6. References_end </body> </html> </notes> <label text="CD209"/> <bbox w="70.0" h="25.0" x="1115.0" y="3277.5"/> </glyph> <glyph class="nucleic acid feature" id="s859_sa759" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PTGS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as PTGS2 (COX2) PMID: PMID:21670502 KLF4 inhibits PTGS2 (COX2) expression. Probably via prevention of NFkB activaiton. PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="70.0" h="25.0" x="4202.5" y="2426.25"/> </glyph> <glyph class="nucleic acid feature" id="s931_sa835" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity References_end </body> </html> </notes> <label text="ICAM1"/> <bbox w="70.0" h="25.0" x="5115.0" y="3159.0"/> </glyph> <glyph class="simple chemical" id="s399_sa332" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="1937.5" y="2982.5"/> </glyph> <glyph class="simple chemical" id="s764_sa333" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Ca2+"/> <bbox w="25.0" h="25.0" x="1855.75" y="2983.0"/> </glyph> <glyph class="phenotype" id="s141_sa113" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:1431106 NO production is associated with tumoricidal activity of macrophages. PMID:20856220 NO production is a marker of M1 phenotype of macrophages. References_end </body> </html> </notes> <label text="NO production"/> <bbox w="176.0" h="42.0" x="3732.0" y="3464.0"/> </glyph> <glyph class="phenotype" id="s157_sa129" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Protumor activity"/> <bbox w="149.0" h="36.0" x="2425.5" y="4037.0"/> </glyph> <glyph class="phenotype" id="s160_sa132" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:20856220 These cells are characterized by their ability to release large amounts of proinflammatory cytokines (such as IL-12, IL-23 and tumor necrosis factor (TNF)), reactive nitrogen intermediates and reactive oxygen intermediates, higher expression of major histocompatibility complex class II and costimulatory molecules, efficient antigen presentation, and microbicidal or tumoricidal activity. M1 macrophages are part of a polarized TH1 response and mediate resistance to intracellular pathogens and tumors and elicit tissue-disruptive reaction. PMID:1431106 Classical activation of macrophages (M1) induces macrophage tumoricidal activity PMID:20338029 The M1 form of tumor-associated macrophages in tumor is positively associated with survival time. PMID:19029990 M1 (classical) activation require both IFNG and TNF. TLR ligand acting in a MyD88-dependent manner will induce the transcription of TNF, which can then cooperate with IFN in an autocrine manner to activate this macrophage population PMID:1679046 Activated monocytes bound to a monolayer of tumor cells more than resting mononuclear phagocytes. References_end </body> </html> </notes> <label text="M1 phenotype of macrophages"/> <bbox w="397.5" h="204.5" x="4022.5" y="3305.0"/> </glyph> <glyph class="phenotype" id="s158_sa130"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:1431106 Classical activation of macrophages (M1) induces macrophage tumoricidal activity PMID:20338029 The M1 form of tumor-associated macrophages in tumor is positively associated with survival time. References_end </body> </html> </notes> <label text="Antitumor activity"/> <bbox w="170.0" h="35.0" x="4115.0" y="4252.5"/> </glyph> <glyph class="phenotype" id="s227_sa213"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Tumor growth, development, methastasis"/> <bbox w="605.0" h="87.0" x="2367.5" y="4606.5"/> </glyph> <glyph class="phenotype" id="s228_sa214"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Tumor cell death"/> <bbox w="478.0" h="90.0" x="4331.0" y="4635.0"/> </glyph> <glyph class="phenotype" id="s379_sa307" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:23124025 MAOA activation incuces generation of intracellular ROS during the oxidation of biogenic amines. PMID:18501881, PMID:7890616 IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway.. References_end </body> </html> </notes> <label text="ROS production"/> <bbox w="97.0" h="33.0" x="3181.5" y="3673.5"/> </glyph> <glyph class="phenotype" id="s380_sa308" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. References_end </body> </html> </notes> <label text="L-ornitine production"/> <bbox w="170.0" h="45.0" x="2665.0" y="3477.5"/> </glyph> <glyph class="phenotype" id="s563_sa484"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Angiogenesis"/> <bbox w="120.0" h="35.0" x="2060.0" y="4212.5"/> </glyph> <glyph class="phenotype" id="s701_sa627" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:12413632 INFG, M-CSF and GM-CSF enhance anti-tumor cytotoxic activity. CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity. References_end </body> </html> </notes> <label text="Macrophage-mediated tumor cytotoxicity"/> <bbox w="290.0" h="55.0" x="4925.0" y="3567.5"/> </glyph> <glyph class="phenotype" id="s702_sa628" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:12413632 Both GM-CSF and M-CSF increase the cytokine production of macrophages and antibody-dependent cellular cytotoxicity (ADCC). PMID:9435247 Macrophage ADCC of tumor target cells requires Fc gamma R types I and III References_end </body> </html> </notes> <label text="Antibody-dependent cellular cytotoxicity"/> <bbox w="300.0" h="55.0" x="5160.0" y="3487.5"/> </glyph> <glyph class="phenotype" id="s895_sa794" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:1679046 Activated monocytes bound to a monolayer of tumor cells more than resting mononuclear phagocytes. PMID:23364881 Cancer cells interact with macrophages through ICAM-1/Mac-1 adhesion molecule References_end </body> </html> </notes> <label text="Macrophage adhesion to tumor cell"/> <bbox w="270.0" h="40.0" x="4785.0" y="3955.0"/> </glyph> <glyph class="phenotype" id="s954_sa858"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPPAGE Maps_Modules_end References_begin: PMID:20856220 M1 macrophages express a lot of proinflammatory cytokines and chemokines. References_end </body> </html> </notes> <label text="Proinflammatory chemokines and cytokines"/> <bbox w="440.0" h="75.0" x="5410.0" y="3967.5"/> </glyph> <glyph class="phenotype" id="s517_sa439" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID: PMID:2422040 MHC II provides antigen presentation by human monocytes. PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. References_end </body> </html> </notes> <label text="Tumor antigen presentation"/> <bbox w="205.0" h="47.5" x="5810.5" y="3261.25"/> </glyph> <glyph class="phenotype" id="s565_sa486" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Tumor invasion"/> <bbox w="120.0" h="40.0" x="2610.0" y="3960.0"/> </glyph> <glyph class="macromolecule" id="s10_sa322" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="600.0" y="2445.0"/> <glyph class="state variable" id="_6a137ec7-9434-41e1-94df-6eda80f3fcc3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="595.0" y="2460.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s10_sa352" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="580.0" y="1980.0"/> <glyph class="state variable" id="_03800e4b-79c5-4214-9542-9fa9fa118bb3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="575.0" y="1995.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s10_sa562" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <clone/> <bbox w="80.0" h="40.0" x="5500.0" y="1685.0"/> <glyph class="state variable" id="_5b8cfb75-56df-47ed-a16b-10d26ee82fd2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5495.0" y="1700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s79_sa56" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL1A"/> <bbox w="80.0" h="40.0" x="4800.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s80_sa57" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: 24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. References_end </body> </html> </notes> <label text="IL1B"/> <clone/> <bbox w="80.0" h="40.0" x="4890.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s80_sa996" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: 24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. References_end </body> </html> </notes> <label text="IL1B"/> <clone/> <bbox w="80.0" h="40.0" x="4120.0" y="1010.0"/> </glyph> <glyph class="macromolecule" id="s117_sa91" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator. References_end </body> </html> </notes> <label text="IL12p40*"/> <bbox w="80.0" h="40.0" x="4617.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s118_sa92" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL8 HUGO:CXCL8 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="80.0" h="40.0" x="4527.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s119_sa93" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:9716487 Interleukin-6-type cytokine signalling acts through the gp130/Jak/STAT pathway. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC References_end </body> </html> </notes> <label text="IL6"/> <bbox w="80.0" h="40.0" x="4436.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s137_sa109" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HMOX1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. HMOX1 mediates IL-10-induced suppression of TNF- production. References_end </body> </html> </notes> <label text="HMOX1"/> <bbox w="80.0" h="40.0" x="3890.0" y="2260.0"/> </glyph> <glyph class="macromolecule" id="s140_sa112" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NOS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:17476345 NOS2, a heme-containing enzyme that catalyzes the synthesis of NO and citrulline from l‐Arg, is expressed by various cells of the immune system, and its activa- tion is considered a hallmark of classically activated macrophages (also known as M1 macrophages), a macrophage subset that pro- duces proinflammatory cytokines and acts as the effector cell in the killing of invading pathogens and tumor cells. PMID:11875494 HMOX1 (HO1) mediates the inhibitory effect of IL10 on LPS-induced NOS2 (INOS) expression. PMID:6357187 Macrophage tumoricidal activity is attributed to NOS2 (iNOS) production. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:21680779, PMID:22816309 Myeloid-derived suppressor cell inhibit the IFN response in immune cells (splenocytes, macrophages) via inhibition of STAT1 phosphorylation by NO (downstream of iNOS).. References_end </body> </html> </notes> <label text="NOS2"/> <bbox w="120.0" h="70.0" x="3800.0" y="3235.0"/> </glyph> <glyph class="macromolecule" id="s142_sa114" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP9 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="80.0" h="40.0" x="2050.0" y="3460.0"/> </glyph> <glyph class="macromolecule" id="s150_sa122" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ARG2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces ARG2 (arginase-2) expression References_end </body> </html> </notes> <label text="ARG2"/> <bbox w="107.0" h="61.0" x="2676.5" y="3179.5"/> </glyph> <glyph class="macromolecule" id="s149_sa121" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ARG1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:12193690, PMID:17476345 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. ARG1 activation has been regarded as one of the most specific markers of M2 macrophages. PMID: 20644162 Human MDSC express AGR1 PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. References_end References_end </body> </html> </notes> <label text="ARG1"/> <bbox w="110.0" h="60.0" x="2528.5" y="3179.5"/> </glyph> <glyph class="macromolecule" id="s218_sa202" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="IL18"/> <bbox w="80.0" h="40.0" x="5075.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s221_sa205" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="80.0" h="40.0" x="4710.5" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s232_sa24" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, PMID:14625680 TNF and IFNG cooperate in the activation of macrophages. References_end </body> </html> </notes> <label text="TNF"/> <bbox w="120.0" h="80.0" x="3960.0" y="2680.0"/> </glyph> <glyph class="macromolecule" id="s310_sa243"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL13 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 IL13 is assosiated with M2 phenotype of macrophages PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620 Other receptor of IL13 is IL13RA2 PMID:18451175, PMID:14657224 IL13 signaling via IL13RA2 induces TGFB production in MDSC. References_end </body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="130.0" y="3005.0"/> </glyph> <glyph class="macromolecule" id="s317_sa250" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. 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References_end </body> </html> </notes> <label text="IL13RA2"/> <bbox w="80.0" h="50.0" x="860.0" y="3060.0"/> <glyph class="unit of information" id="_092b5265-f55a-4309-af34-c6add175ece5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="877.5" y="3055.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s388_sa319" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. 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JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. 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JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. 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IL-13 significantly inhibits the ROS generation in all macrophage types, probably, via PLC/Ca2+/cAMP/PKA pathway PMID:10925299 IL13 activates Arginase activity downstream of cAMP/PKA References_end </body> </html> </notes> <label text="PKA*"/> <bbox w="80.0" h="40.0" x="2310.0" y="3080.0"/> </glyph> <glyph class="macromolecule" id="s396_sa338" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="1538.5" y="2605.0"/> <glyph class="state variable" id="_d5b67a31-6789-4a70-b8f2-2311f313f262"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1533.5" y="2620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s398_sa331" compartmentRef="c9_ca9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITPR1 HUGO:ITPR2 HUGO:ITPR3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="IP3R*"/> <bbox w="80.0" h="50.0" x="1653.75" y="2931.5"/> <glyph class="unit of information" id="_0a9fb864-7ee2-49e1-8899-1eae498c41f9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1671.25" y="2926.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s408_sa329" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PLCG1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="1540.0" y="2685.0"/> <glyph class="state variable" id="_3306eaa3-d621-496e-be63-c7ea81dce081"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1532.5" y="2700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s443_sa370" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAOA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:23124025 MAOA activation incuces generation of intracellular ROS during the oxidation of biogenic amines. References_end </body> </html> </notes> <label text="MAOA"/> <bbox w="80.0" h="40.0" x="2900.0" y="3650.0"/> </glyph> <glyph class="macromolecule" id="s449_sa376" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:DUSP1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16184516 In silico analysis identified a STAT6 binding site at position +99 (relative to the transcriptional start site) of the mouse DUSP1 promoter. References_end </body> </html> </notes> <label text="DUSP1"/> <bbox w="80.0" h="40.0" x="1262.5" y="2572.0"/> </glyph> <glyph class="macromolecule" id="s452_sa379" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TIMP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23124025 IL4 induces expression of TIMP3 via JAK1 pathway References_end </body> </html> </notes> <label text="TIMP3"/> <bbox w="80.0" h="40.0" x="1360.0" y="2570.0"/> </glyph> <glyph class="macromolecule" id="s466_sa394" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). 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IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. 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PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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References_end </body> </html> </notes> <label text="CD86"/> <bbox w="80.0" h="40.0" x="5720.0" y="2890.0"/> <glyph class="unit of information" id="_e7a7c903-3a45-4b6a-90f2-4dbe043fdfee"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5737.5" y="2885.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s568_sa490" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:VEGFA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="80.0" h="40.0" x="1905.0" y="3451.5"/> </glyph> <glyph class="macromolecule" id="s594_sa517" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAX Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as CD11c (ITGAX) PMID:1679046 Probably all CD11 proteins (a,b,c) participates in macrophage tumoricidal activity. References_end </body> </html> </notes> <label text="CD11c*"/> <bbox w="80.0" h="50.0" x="4850.0" y="3208.5"/> <glyph class="unit of information" id="_5b2af436-160b-43c4-9fd5-7e647955c2d2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4867.5" y="3203.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s595_sa518" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21765015, PMID:22869907 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production. CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. specific inhibition of PHD3 increases VEGF production. References_end </body> </html> </notes> <label text="trVEGFR1*"/> <bbox w="80.0" h="40.0" x="4210.0" y="3180.0"/> <glyph class="unit of information" id="_c603674b-305e-45ee-969a-5a586d7e818a"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4225.0" y="3175.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s683_sa607" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="80.0" h="40.0" x="4720.0" y="2833.5"/> </glyph> <glyph class="macromolecule" id="s697_sa623" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1RN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="IL1RN"/> <bbox w="80.0" h="40.0" x="2516.0" y="2798.5"/> </glyph> <glyph class="macromolecule" id="s698_sa624" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CCL4"/> <bbox w="80.0" h="40.0" x="4817.0" y="2833.5"/> </glyph> <glyph class="macromolecule" id="s751_sa404" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SUMO1 HUGO:SUMO2 HUGO:SUMO3 HUGO:SUMO4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <label text="SUMO*"/> <bbox w="80.0" h="40.0" x="3180.0" y="2835.0"/> </glyph> <glyph class="macromolecule" id="s761_sa522"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21765015, PMID:22869907 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production. CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. specific inhibition of PHD3 increases VEGF production. References_end </body> </html> </notes> <label text="trVEGFR1*"/> <bbox w="80.0" h="40.0" x="1890.0" y="4270.0"/> <glyph class="unit of information" id="_6d99fe18-3f62-4b84-841a-534149296215"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1905.0" y="4265.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s762_sa491"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:VEGFA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="80.0" h="40.0" x="1890.0" y="4200.0"/> </glyph> <glyph class="macromolecule" id="s765_sa684" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CREB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. References_end </body> </html> </notes> <label text="CREB1"/> <bbox w="80.0" h="40.0" x="3605.0" y="2428.5"/> <glyph class="state variable" id="_7d7a1dec-ddbc-415a-b2a9-4f40534d4e52"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3600.0" y="2443.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s766_sa685" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CREB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. References_end </body> </html> </notes> <label text="CREB1"/> <bbox w="80.0" h="40.0" x="3605.0" y="2528.5"/> <glyph class="state variable" id="_61d49f3b-9be6-4b49-aa21-3aecfa509a0b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3597.5" y="2543.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s771_sa690" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. References_end </body> </html> </notes> <label text="AP1*"/> <clone/> <bbox w="80.0" h="40.0" x="3275.0" y="2628.5"/> </glyph> <glyph class="macromolecule" id="s771_sa691" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUN HUGO:JUNB HUGO:JUND HUGO:JBP1 HUGO:FOS HUGO:FOSB HUGO:FOSL1 HUGO:FOSL2 HUGO:MAF HUGO:MAFB HUGO:MAFA HUGO:MAFG HUGO:MAFK HUGO:MAFF HUGO:NRL HUGO:ATF1 HUGO:ATF2 HUGO:ATF3 HUGO:BATF HUGO:BATF2 HUGO:BATF3 HUGO:JDP2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. References_end </body> </html> </notes> <label text="AP1*"/> <clone/> <bbox w="80.0" h="40.0" x="3275.0" y="2728.5"/> </glyph> <glyph class="macromolecule" id="s779_sa694" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNFRSF1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR2*"/> <bbox w="80.0" h="50.0" x="6170.0" y="2405.0"/> <glyph class="unit of information" id="_36f7aa0a-2bf5-4eb0-8536-d91d325025a7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6187.5" y="2400.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s784_sa699" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TRAF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNFR2 interacts with TRAF2 and TRAF1. References_end </body> </html> </notes> <label text="TRAF1"/> <bbox w="80.0" h="40.0" x="5740.0" y="2380.0"/> </glyph> <glyph class="macromolecule" id="s822_sa260" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. INFG signaling down regulates JUN protein level References_end </body> </html> </notes> <label text="JUN"/> <bbox w="80.0" h="40.0" x="3185.0" y="2538.5"/> <glyph class="state variable" id="_3c881a5c-8763-4992-9384-4e185fffb6f2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3177.5" y="2553.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s847_sa746" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL23A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL23A"/> <bbox w="80.0" h="40.0" x="5163.0" y="2653.5"/> </glyph> <glyph class="macromolecule" id="s861_sa761" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PTGS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as PTGS2 (COX2) PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="80.0" h="40.0" x="4200.0" y="2530.0"/> </glyph> <glyph class="macromolecule" id="s867_sa768" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. References_end </body> </html> </notes> <label text="STAB1"/> <bbox w="80.0" h="50.0" x="1200.0" y="3455.0"/> <glyph class="unit of information" id="_74b2e91c-0e5c-4052-879f-f63c6d6721e6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1217.5" y="3450.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s870_sa771" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="FCER2"/> <bbox w="80.0" h="50.0" x="1290.0" y="3495.0"/> <glyph class="unit of information" id="_0b7c8551-6db2-4b2e-a431-f26512fa3497"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1307.5" y="3490.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s888_sa787" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAX HUGO:ITGAM HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:1679046 Probably all CD11 proteins (a,b,c) participates in macrophage tumoricidal activity. References_end </body> </html> </notes> <label text="CD11*"/> <bbox w="80.0" h="50.0" x="4810.0" y="3425.0"/> <glyph class="unit of information" id="_2391e033-b330-4e79-9563-95a528137ad0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4827.5" y="3420.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s889_sa788" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAM Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21383238 CD33 and CD11b are typical markers of MDSC cells PMID:1679046 Probably all CD11 proteins (a,b,c) participates in macrophage tumoricidal activity. References_end </body> </html> </notes> <label text="CD11b*"/> <bbox w="80.0" h="50.0" x="4770.0" y="3208.5"/> <glyph class="unit of information" id="_5492a0f3-95c8-4a0f-80be-604b18ef9cb4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4787.5" y="3203.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s890_sa789" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGAL Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:1679046 Probably all CD11 proteins (a,b,c) participates in macrophage tumoricidal activity. References_end </body> </html> </notes> <label text="CD11a*"/> <bbox w="80.0" h="50.0" x="4680.0" y="3205.0"/> <glyph class="unit of information" id="_ebdbedd5-1ae9-44aa-aafe-a20a0c3dbeeb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4697.5" y="3200.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s873_sa774" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotoxicity. PMID:1679046 INFG apregulates CD18 surface expression. Inhibition of CD18 inhibits monocyte binding to tumor target cells and tumoricidal activity. References_end </body> </html> </notes> <label text="CD18*"/> <bbox w="80.0" h="50.0" x="4560.0" y="3450.0"/> <glyph class="unit of information" id="_95a86a4d-00a8-4f61-a612-cecb0361b0e8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4577.5" y="3445.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s897_sa796" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FCGR1A HUGO:FCGR1B HUGO:FCGR1C Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:9435247 Macrophage ADCC of tumor target cells requires Fc gamma R types I and III (CD64 and CD16) References_end </body> </html> </notes> <label text="CD64*"/> <bbox w="80.0" h="50.0" x="5160.0" y="3415.0"/> <glyph class="unit of information" id="_4cbab132-c5b0-4e89-bb3d-df4ff0785357"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5177.5" y="3410.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s899_sa798" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FCGR3A HUGO:FCGR3B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:9435247 Macrophage ADCC of tumor target cells requires Fc gamma R types I and III (CD64 and CD16) References_end </body> </html> </notes> <label text="CD16*"/> <bbox w="80.0" h="50.0" x="5260.0" y="3365.0"/> <glyph class="unit of information" id="_7474f5ba-894b-4668-bfca-ebfb3beb3637"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5277.5" y="3360.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s919_sa820" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD209 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expresion of CD209 downstream of IL4, probably via STAT6. References_end </body> </html> </notes> <label text="CD209"/> <bbox w="80.0" h="50.0" x="1110.0" y="3415.0"/> <glyph class="unit of information" id="_ebc61403-def2-4a8d-93c3-329d9dbaf857"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1127.5" y="3410.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s933_sa837" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity PMID:1673988 Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. PMID:23364881 Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion PMID:7512027 INFG up-regulates ICAM1 and CD80 (B7) surface expression in monocytes. And IL10 inhibit it. 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References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="80.0" h="40.0" x="5723.0" y="3635.0"/> </glyph> <glyph class="macromolecule" id="s937_sa841"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="80.0" h="40.0" x="5613.0" y="3635.0"/> </glyph> <glyph class="macromolecule" id="s938_sa842"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL7 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CCL7"/> <bbox w="80.0" h="40.0" x="5513.0" y="3635.0"/> </glyph> <glyph class="macromolecule" id="s939_sa843" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="80.0" h="40.0" x="5393.0" y="3635.0"/> </glyph> <glyph class="macromolecule" id="s940_sa844" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="80.0" h="40.0" x="5293.0" y="3635.0"/> </glyph> <glyph class="macromolecule" id="s941_sa845"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL23A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL23A"/> <bbox w="80.0" h="40.0" x="5920.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s942_sa846"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="80.0" h="40.0" x="5467.5" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s943_sa847"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="IL18"/> <bbox w="80.0" h="40.0" x="5832.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s946_sa850"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL8 HUGO:CXCL8 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="80.0" h="40.0" x="5284.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s947_sa851"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator. References_end </body> </html> </notes> <label text="IL12p40*"/> <bbox w="80.0" h="40.0" x="5374.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s948_sa852"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: 24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="80.0" h="40.0" x="5647.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s949_sa853"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL1A"/> <bbox w="80.0" h="40.0" x="5557.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s950_sa854"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL9 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CXCL9"/> <bbox w="80.0" h="40.0" x="6080.0" y="3625.0"/> </glyph> <glyph class="macromolecule" id="s951_sa855"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="80.0" h="40.0" x="6200.0" y="3625.0"/> </glyph> <glyph class="macromolecule" id="s952_sa856" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL9 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CXCL9"/> <bbox w="80.0" h="40.0" x="4920.0" y="2840.0"/> </glyph> <glyph class="macromolecule" id="s953_sa857" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="80.0" h="40.0" x="5020.0" y="2840.0"/> </glyph> <glyph class="macromolecule" id="s955_sa859"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induced IFNB expression through IRF1. TNF-induced Ifnb1 expression was completely abrogated in IRF1-deficient macrophages. References_end </body> </html> </notes> <label text="INFB1"/> <bbox w="80.0" h="40.0" x="6100.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s956_sa860"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induces IFNA expression in macrophages References_end </body> </html> </notes> <label text="INFA1"/> <bbox w="80.0" h="40.0" x="6010.0" y="3795.0"/> </glyph> <glyph class="macromolecule" id="s957_sa861" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ABCB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="ABCB1"/> <bbox w="80.0" h="40.0" x="4160.0" y="2840.0"/> </glyph> <glyph class="macromolecule" id="s968_sa872" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CYP1B1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="CYP1B1"/> <bbox w="80.0" h="40.0" x="2206.0" y="2795.0"/> </glyph> <glyph class="macromolecule" id="s969_sa873" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL24 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="CCL24"/> <bbox w="80.0" h="40.0" x="2306.0" y="2795.0"/> </glyph> <glyph class="macromolecule" id="s970_sa874" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MPP6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="MPP6"/> <bbox w="80.0" h="40.0" x="2416.0" y="2795.0"/> </glyph> <glyph class="macromolecule" id="s971_sa876" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL18 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 PMID:22117697 References_end </body> </html> </notes> <label text="CCL18"/> <bbox w="80.0" h="40.0" x="1590.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s972_sa877" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL17 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 References_end </body> </html> </notes> <label text="CCL17"/> <bbox w="80.0" h="40.0" x="1480.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s973_sa878" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL22 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 References_end </body> </html> </notes> <label text="CCL22"/> <bbox w="80.0" h="40.0" x="1680.0" y="3320.0"/> </glyph> <glyph class="nucleic acid feature" id="s27_sa23" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:1431106 TNF is ploinfammatory cytokine induced tumoricidal activity of macrophages References_end </body> </html> </notes> <label text="TNF"/> <bbox w="125.0" h="62.5" x="3955.0" y="2580.0"/> <glyph class="unit of information" id="_40f6ebf9-5fc5-4ed1-a043-5a2b9f5df4c5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4007.5" y="2575.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s77_sa54" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL1A"/> <bbox w="90.0" h="25.0" x="4795.0" y="2591.0"/> <glyph class="unit of information" id="_f87091f1-4eda-4b50-bf64-1f71bf3e0b07"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4830.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s78_sa55" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:MDSC Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1B. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="90.0" h="25.0" x="4885.0" y="2591.0"/> <glyph class="unit of information" id="_6b409247-dd4d-41a5-a244-f91bb2856665"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4920.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s114_sa88" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator. References_end </body> </html> </notes> <label text="IL12p40*"/> <bbox w="90.0" h="25.0" x="4612.0" y="2591.0"/> <glyph class="unit of information" id="_b5abaac9-858b-4ea7-acb6-96d05dd83f08"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4647.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s115_sa89" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL8 HUGO:IL8 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 References_end </body> </html> </notes> <label text="IL8*"/> <bbox w="90.0" h="25.0" x="4522.0" y="2591.0"/> <glyph class="unit of information" id="_dc8b6d89-eb1f-4e32-8879-3922d3cb955d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4557.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s116_sa90" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:9743347 IL-13 blocks NF-κB-dependent production of IL6 PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC References_end </body> </html> </notes> <label text="IL6"/> <bbox w="90.0" h="25.0" x="4431.0" y="2591.0"/> <glyph class="unit of information" id="_19329a4a-74a5-4418-b3f0-504ec7a34d00"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4466.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s136_sa108" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HMOX1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. References_end </body> </html> </notes> <label text="HMOX1"/> <bbox w="90.0" h="25.0" x="3878.0" y="2211.5"/> <glyph class="unit of information" id="_563b5a7f-6f71-43e3-a1fc-be683c0a3b60"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3913.0" y="2206.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s139_sa111" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NOS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:17476345 NOS2, a heme-containing enzyme that catalyzes the synthesis of NO and citrulline from l‐Arg, is expressed by various cells of the immune system, and its activa- tion is considered a hallmark of classically activated macrophages (also known as M1 macrophages), a macrophage subset that pro- duces proinflammatory cytokines and acts as the effector cell in the killing of invading pathogens and tumor cells. References_end </body> </html> </notes> <label text="NOS2"/> <bbox w="126.0" h="52.5" x="3794.0" y="3125.0"/> <glyph class="unit of information" id="_5e664054-91cd-4e7b-874b-398d26b5d339"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3847.0" y="3120.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s143_sa115" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP9 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="90.0" h="25.0" x="2045.0" y="3387.5"/> <glyph class="unit of information" id="_df18b39f-4790-4801-b570-ab35b1315255"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2080.0" y="3382.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s147_sa119" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ARG1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces arginase-2 expression Up-regulation of IL4RA by IL10 correlates with increased IL4-dependent expression of arginase-1 (ARG1). References_end </body> </html> </notes> <label text="ARG1"/> <bbox w="127.0" h="43.5" x="2520.25" y="3099.5"/> <glyph class="unit of information" id="_1a7ac947-3725-4bc1-860e-6ecacb4a38f0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2573.75" y="3094.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s148_sa120" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ARG2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION Maps_Modules_end References_begin: PMID:12193690 A hallmark of “alternative activation” (M2) of macrophages is high arginase activity, which competes with inducible NO synthase for L-arginine, the common substrate of both enzymes. IL-10 induces ARG2 (arginase-2) expression References_end </body> </html> </notes> <label text="ARG2"/> <bbox w="124.0" h="45.5" x="2668.25" y="3099.5"/> <glyph class="unit of information" id="_5786c2ea-965f-459f-851d-5270d9dca136"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2720.25" y="3094.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s155_sa127" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="CSF3"/> <bbox w="90.0" h="25.0" x="4978.0" y="2591.0"/> <glyph class="unit of information" id="_d9b260b6-d519-482a-a79c-2c6998eb0210"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5013.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s217_sa201" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL18 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="IL18"/> <bbox w="90.0" h="25.0" x="5070.0" y="2591.0"/> <glyph class="unit of information" id="_2e1bb3ad-ea15-45cd-8991-70c07c08aa9c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5105.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s220_sa204" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL12A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IL12p35*"/> <bbox w="90.0" h="25.0" x="4705.5" y="2591.0"/> <glyph class="unit of information" id="_568ad44e-5e7c-4f3c-ab2f-a768a64b0a1f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4740.5" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s319_sa252" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. 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PMID:12928384 GM-CSF increases types I and III CIITA mRNA in primary human monocytes, while IFNG increases types III and IV CIITA transcripts References_end </body> </html> </notes> <label text="CIITA"/> <bbox w="90.0" h="25.0" x="5275.0" y="2902.5"/> <glyph class="unit of information" id="_797ca35d-585a-4d35-ad16-b2a7d3190f27"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5310.0" y="2897.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s519_sa441" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CYP1B1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CYP1B1"/> <bbox w="90.0" h="25.0" x="2201.0" y="2736.0"/> <glyph class="unit of information" id="_ce92ce05-feee-4b2a-a265-41467fb7b906"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2236.0" y="2731.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s521_sa443" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL24 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="CCL24"/> <bbox w="90.0" h="25.0" x="2301.0" y="2742.0"/> <glyph class="unit of information" id="_52cb1647-cb09-4024-86e1-425b4b2d2452"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2336.0" y="2737.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s523_sa445" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MPP6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="MPP6"/> <bbox w="90.0" h="25.0" x="2411.0" y="2742.0"/> <glyph class="unit of information" id="_b7328712-7af5-40b8-865b-a795a8f9d054"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2446.0" y="2737.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s525_sa447" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL1RN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <label text="IL1RN"/> <bbox w="90.0" h="25.0" x="2511.0" y="2746.0"/> <glyph class="unit of information" id="_fd305d9d-6262-44f4-8647-eb2927e254af"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2546.0" y="2741.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s537_sa458" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD40 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. References_end </body> </html> </notes> <label text="CD40"/> <bbox w="90.0" h="25.0" x="5475.0" y="2887.5"/> <glyph class="unit of information" id="_3e8b52f1-4055-4e5b-a357-253139e48427"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5510.0" y="2882.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s538_sa459" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD80 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. References_end </body> </html> </notes> <label text="CD80"/> <bbox w="90.0" h="25.0" x="5515.0" y="2837.5"/> <glyph class="unit of information" id="_8e49601e-fee8-4623-a367-cd539dbf4f79"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5550.0" y="2832.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s539_sa460" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD86 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID:12101276 CD40, CD80 and CD86 participate in antigen presentation by macrophages. References_end </body> </html> </notes> <label text="CD86"/> <bbox w="90.0" h="25.0" x="5545.0" y="2797.5"/> <glyph class="unit of information" id="_92a4789e-6c8b-4599-86c1-11b8e61df601"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5580.0" y="2792.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s567_sa489" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:VEGFA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="90.0" h="25.0" x="1905.0" y="3387.5"/> <glyph class="unit of information" id="_3e841a38-1ad9-491a-9652-eddced5ea462"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1940.0" y="3382.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s685_sa609" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="90.0" h="25.0" x="4715.0" y="2781.0"/> <glyph class="unit of information" id="_a8382436-a2d0-462b-91ed-e4756961db9b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4750.0" y="2776.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s699_sa625" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCL4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine CCL4 (MIP1B). References_end </body> </html> </notes> <label text="CCL4"/> <bbox w="90.0" h="25.0" x="4815.0" y="2781.0"/> <glyph class="unit of information" id="_8fd7b4aa-7777-440d-90a5-37798e1a0d56"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4850.0" y="2776.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s768_sa687" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FOS Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="FOS"/> <bbox w="90.0" h="25.0" x="3430.0" y="2396.0"/> <glyph class="unit of information" id="_d198ab40-2451-4a1b-93b8-71c3a5eb72b4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3465.0" y="2391.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s770_sa689" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JUN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="JUN"/> <bbox w="90.0" h="25.0" x="3180.0" y="2406.0"/> <glyph class="unit of information" id="_230e1cd4-9b74-41c3-b7fe-e52b478a8d9a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3215.0" y="2401.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s848_sa747" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL23A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. References_end </body> </html> </notes> <label text="IL23A"/> <bbox w="90.0" h="25.0" x="5158.0" y="2591.0"/> <glyph class="unit of information" id="_2d854117-5a70-43b0-8a89-0ec9ff0436ce"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5193.0" y="2586.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s596_sa519" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FLT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:21765015, PMID:22869907 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production. CSF2 upregulates expression of soluble form of VEGFR (sVEGFR-1) wich inhibits VEGF signaling via HIF2a. specific inhibition of PHD3 increases VEGF production. References_end </body> </html> </notes> <label text="VEGFR1*"/> <bbox w="90.0" h="25.0" x="4205.0" y="3107.5"/> <glyph class="unit of information" id="_4061d4ca-16b2-4347-80b2-e4be9df7dd6c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4240.0" y="3102.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s860_sa760" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PTGS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as PTGS2 (COX2) PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="90.0" h="25.0" x="4192.5" y="2486.25"/> <glyph class="unit of information" id="_c4603056-7e7a-49a3-9823-c2046c592eed"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4227.5" y="2481.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s868_sa769" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. References_end </body> </html> </notes> <label text="STAB1"/> <bbox w="90.0" h="25.0" x="1195.0" y="3327.5"/> <glyph class="unit of information" id="_c873098c-7c2e-43cb-87f2-3c88e5496a0f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1230.0" y="3322.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s871_sa772" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FCER2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, FCER2 (CD23). References_end </body> </html> </notes> <label text="FCER2"/> <bbox w="90.0" h="25.0" x="1285.0" y="3327.5"/> <glyph class="unit of information" id="_c3e10944-9a63-4118-baa7-2a41a6a627a7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1320.0" y="3322.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s874_sa775" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ITGB2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity References_end </body> </html> </notes> <label text="CD18"/> <bbox w="90.0" h="25.0" x="4555.0" y="3342.5"/> <glyph class="unit of information" id="_554cd7e6-478e-4e97-af7e-2fd8013089c8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4590.0" y="3337.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s921_sa822" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD209 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expresion of CD209 downstream of IL4, probably via STAT6. References_end </body> </html> </notes> <label text="CD209"/> <bbox w="90.0" h="25.0" x="1105.0" y="3327.5"/> <glyph class="unit of information" id="_992e8f94-b3c9-475c-a81f-b7b604f1786d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1140.0" y="3322.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s932_sa836" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ICAM1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 CD18/CD11-ICAM-1 adhesion between effector and target cells plays an important role in macrophage-mediated tumor cytotox- icity References_end </body> </html> </notes> <label text="ICAM1"/> <bbox w="90.0" h="25.0" x="5105.0" y="3207.5"/> <glyph class="unit of information" id="_c2e60116-1972-48f0-9c15-72a768ba4232"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5140.0" y="3202.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s351_sa279" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. References_end </body> </html> </notes> <label text="L-arginine"/> <bbox w="100.0" h="28.0" x="3120.0" y="2966.0"/> </glyph> <glyph class="simple chemical" id="s352_sa280" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="NO"/> <bbox w="70.0" h="25.0" x="3540.0" y="3446.0"/> </glyph> <glyph class="simple chemical" id="s354_sa282" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="NADPH"/> <bbox w="70.0" h="25.0" x="3545.0" y="3147.5"/> </glyph> <glyph class="simple chemical" id="s368_sa295" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="NADP+"/> <bbox w="70.0" h="25.0" x="3380.0" y="3346.0"/> </glyph> <glyph class="simple chemical" id="s369_sa296" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="L-citrulin"/> <bbox w="70.0" h="25.0" x="3370.0" y="3476.0"/> </glyph> <glyph class="simple chemical" id="s370_sa297" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Urea"/> <bbox w="70.0" h="25.0" x="2735.0" y="3347.5"/> </glyph> <glyph class="simple chemical" id="s371_sa298" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="L-ornitine"/> <bbox w="70.0" h="25.0" x="2815.0" y="3377.5"/> </glyph> <glyph class="simple chemical" id="s377_sa304" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="O2-"/> <bbox w="70.0" h="25.0" x="3062.0" y="3586.5"/> </glyph> <glyph class="simple chemical" id="s353_sa281" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="O2"/> <clone/> <bbox w="70.0" h="25.0" x="3475.0" y="3117.5"/> </glyph> <glyph class="simple chemical" id="s353_sa305" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. References_end </body> </html> </notes> <label text="O2"/> <clone/> <bbox w="70.0" h="25.0" x="3185.0" y="3527.5"/> </glyph> <glyph class="simple chemical" id="s375_sa302" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="H2O2"/> <bbox w="70.0" h="25.0" x="3191.0" y="3588.5"/> </glyph> <glyph class="simple chemical" id="s378_sa306" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="hydroxyl"/> <bbox w="70.0" h="25.0" x="3315.0" y="3587.5"/> </glyph> <glyph class="simple chemical" id="s393_sa325" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="ATP"/> <bbox w="70.0" h="25.0" x="1995.0" y="2959.0"/> </glyph> <glyph class="simple chemical" id="s394_sa326" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <label text="cAMP"/> <bbox w="70.0" h="25.0" x="1995.0" y="3032.5"/> </glyph> <glyph class="simple chemical" id="s397_sa330" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="IP3"/> <bbox w="70.0" h="25.0" x="1662.0" y="2816.5"/> </glyph> <glyph class="simple chemical" id="s405_sa336" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="PI4,5-P2"/> <bbox w="70.0" h="25.0" x="1655.0" y="2656.5"/> </glyph> <glyph class="simple chemical" id="s406_sa337" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="1579.0" y="2774.5"/> </glyph> <glyph class="phenotype" id="s562_sa483"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:17164174 Hypoxia (0.5% O2) elicits macrophages to produce higher levels of O2*-, TGF-beta, and VEGF than normoxia. References_end </body> </html> </notes> <label text="Hypoxia"/> <bbox w="120.0" h="35.0" x="3010.0" y="22.5"/> </glyph> <glyph class="nucleic acid feature" id="s786_sa700" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12193701 INFG upregulates TNFR1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="70.0" h="25.0" x="5455.0" y="1862.5"/> </glyph> <glyph class="macromolecule" id="s995_sa902"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="1350.0" y="420.0"/> </glyph> <glyph class="macromolecule" id="s994_sa901" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SLC3A2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98). References_end </body> </html> </notes> <label text="SLC3A2"/> <bbox w="80.0" h="50.0" x="1460.0" y="730.0"/> <glyph class="unit of information" id="_ef93424e-a35b-4cf0-9071-9b86150bd49c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1477.5" y="725.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s958_sa863" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:GRB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:19109239 Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="800.0" y="1970.0"/> </glyph> <glyph class="macromolecule" id="s924_sa825" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KLF4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:21670502 KLF4 together with STAT6 upregulates expression of PPARG and ARG1 downstream of IL4. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. KLF4 inhibits PTGS2 (COX2) expression. Probably via prevention of NFkB activaiton. References_end </body> </html> </notes> <label text="KLF4"/> <bbox w="80.0" h="40.0" x="1570.0" y="1860.0"/> </glyph> <glyph class="nucleic acid feature" id="s923_sa824" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KLF4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:21670502 IL4 upregulates expression of KLF4 via STAT6 in M2 macrophages. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. References_end </body> </html> </notes> <label text="KLF4"/> <bbox w="90.0" h="25.0" x="1455.0" y="1877.5"/> <glyph class="unit of information" id="_ba0bf282-e6bd-49df-9f76-94429ee9e484"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1490.0" y="1872.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s922_sa823" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KLF4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:21670502 IL4 upregulates expression of KLF4 via STAT6 in M2 macrophages. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. References_end </body> </html> </notes> <label text="KLF4"/> <bbox w="70.0" h="25.0" x="1355.0" y="1877.5"/> </glyph> <glyph class="nucleic acid feature" id="s918_sa817" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expression of STAT6 ans enhances downstream IL4 signaling. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="90.0" h="25.0" x="935.0" y="2211.0"/> <glyph class="unit of information" id="_3323eda3-4cbb-4422-83d2-557532c787d1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="970.0" y="2206.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s917_sa816" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 MYC upregulates expression of STAT6 ans enhances downstream IL4 signaling. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="70.0" h="25.0" x="815.0" y="2211.0"/> </glyph> <glyph class="macromolecule" id="s916_sa815" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MYC Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. References_end </body> </html> </notes> <label text="MYC"/> <bbox w="80.0" h="40.0" x="1880.0" y="1740.0"/> </glyph> <glyph class="nucleic acid feature" id="s915_sa814" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MYC Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. References_end </body> </html> </notes> <label text="MYC"/> <bbox w="90.0" h="25.0" x="1735.0" y="1747.5"/> <glyph class="unit of information" id="_41ed930c-601e-4b6c-9a7c-06ebcf988247"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1770.0" y="1742.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s914_sa813" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MYC Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:22067385 c-MYC expression is assosiated with M2 type of macrophages. IL4 induces MYC expression in macrophages. MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:11340171 MYC inhibits myeloid cells differentiation. References_end </body> </html> </notes> <label text="MYC"/> <bbox w="70.0" h="25.0" x="1745.0" y="1677.5"/> </glyph> <glyph class="macromolecule" id="s913_sa812" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15749884 IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="MAF"/> <bbox w="80.0" h="40.0" x="1570.0" y="1780.0"/> </glyph> <glyph class="nucleic acid feature" id="s912_sa811" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15749884 IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="MAF"/> <bbox w="70.0" h="25.0" x="1355.0" y="1797.5"/> </glyph> <glyph class="nucleic acid feature" id="s911_sa810" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15749884 IL-4 dose dependently stimulated c-Maf expression (both short and long forms) in resting monocytes.c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <label text="MAF"/> <bbox w="90.0" h="25.0" x="1455.0" y="1787.5"/> <glyph class="unit of information" id="_7a2e2ac6-e9e4-4108-a747-96d716b0c460"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1490.0" y="1782.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s851_sa751" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFBR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12809600 A TGFB ligand initiates signaling by binding to and bringing together type I and type II receptor serine/threonine kinases on the cell surface. References_end </body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="1150.0" y="830.0"/> <glyph class="unit of information" id="_93de431e-440f-4f74-8f6c-568921aee835"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1167.5" y="825.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s772_sa692" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="124.5" h="80.0" x="1257.75" y="1990.0"/> <glyph class="unit of information" id="_9b9cf0be-3671-48ef-9f66-6facf81d4d1b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="1310.0" y="1985.0"/> </glyph> <glyph class="state variable" id="_e0fda1b5-7e19-400d-b104-1c4b23593c30"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1250.25" y="2024.9363"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s163_sa135" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 IL10 inhibits miR155 expression via STAT3. 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="1385.0" y="1497.5"/> <glyph class="unit of information" id="_9646da5a-5877-4eb9-a185-69762db3f348"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1415.0" y="1492.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s581_sa504"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCL12 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:20644254 CXCR4, the receptor for the chemokine CXCL12 (also known as SDF-1), also plays an important role in facilitating macrophage migration in vivo. PMID:22025564 PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12 by tumor cells. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="2200.0" y="310.0"/> </glyph> <glyph class="nucleic acid feature" id="s579_sa502" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCR4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="90.0" h="25.0" x="2285.0" y="787.5"/> <glyph class="unit of information" id="_99be42d6-571e-435e-b16b-28770322fc56"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2320.0" y="782.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s578_sa501" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CXCR4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. PMID:22025564 PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="80.0" h="50.0" x="2280.0" y="655.0"/> <glyph class="unit of information" id="_55f6b4e9-cab1-4c38-b854-c66076bccaa4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2297.5" y="650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s564_sa485"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297, PMID:22461508, PMID:8195715 MIF is expresed by macrophages PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression and activates tumor invasion. PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86. MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD206, CD23. References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="1460.0" y="390.0"/> </glyph> <glyph class="macromolecule" id="s548_sa469" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="1170.0" y="900.0"/> <glyph class="unit of information" id="_463d2d8c-31af-483f-bc52-33e7b21663f4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1187.5" y="895.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s547_sa468"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. References_end </body> </html> </notes> <label text="TGFB1"/> <bbox w="80.0" h="40.0" x="1110.0" y="535.0"/> </glyph> <glyph class="nucleic acid feature" id="s506_sa426" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KDM6B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. References_end </body> </html> </notes> <label text="KDM6B"/> <bbox w="90.0" h="25.0" x="1730.0" y="2266.0"/> <glyph class="unit of information" id="_1408b666-fff1-4b3f-84b5-f7a1b8b5fedb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1765.0" y="2261.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s505_sa425" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KDM6B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19567879 IL-4 via STAT6 upregulates expression of H3K27me2/3-specific demethylase KDM6B ( Jmjd3). References_end </body> </html> </notes> <label text="KDM6B"/> <bbox w="70.0" h="25.0" x="1740.0" y="2196.0"/> </glyph> <glyph class="nucleic acid feature" id="s457_sa385" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="PPARG"/> <bbox w="90.0" h="25.0" x="1925.0" y="1937.5"/> <glyph class="unit of information" id="_f0f639ca-df28-4c0d-b5be-4b972d6b2321"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1960.0" y="1932.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s456_sa384" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10432118, PMID:21093321 IL4 upregulates expression of PPARG via JAK3/STAT6 pathway. PMID: PMID:21670502 KLF4 together with STAT6 upregulates expression of PPARG and ARG1 downstream of IL4. References_end </body> </html> </notes> <label text="PPARG"/> <bbox w="70.0" h="25.0" x="1935.0" y="1877.5"/> </glyph> <glyph class="simple chemical" id="s455_sa383" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="linoleic acid"/> <bbox w="70.0" h="25.0" x="1835.0" y="1977.5"/> </glyph> <glyph class="macromolecule" id="s453_sa382" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4. References_end </body> </html> </notes> <label text="PPARG"/> <clone/> <bbox w="80.0" h="40.0" x="1945.0" y="2088.5"/> </glyph> <glyph class="macromolecule" id="s453_sa380" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4. References_end </body> </html> </notes> <label text="PPARG"/> <clone/> <bbox w="80.0" h="40.0" x="1940.0" y="2000.0"/> </glyph> <glyph class="simple chemical" id="s454_sa381" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="13(S)-HPODE"/> <bbox w="70.0" h="25.0" x="1835.0" y="2047.5"/> </glyph> <glyph class="macromolecule" id="s440_sa367" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ALOX15 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10432118 ALOX15 activation results in induction of CD36 expression downstream of IL4 and IL13 via PRARG Linoleic acid is oxygenated by ALOX15 to 13-HODE which activates PPARG. References_end </body> </html> </notes> <label text="ALOX15"/> <bbox w="80.0" h="40.0" x="1730.0" y="1980.0"/> </glyph> <glyph class="nucleic acid feature" id="s439_sa366" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ALOX15 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="ALOX15"/> <bbox w="90.0" h="25.0" x="1731.0" y="1927.005"/> <glyph class="unit of information" id="_1d839103-9022-4e19-ba00-f818c0594e11"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1766.0" y="1922.005"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s438_sa365" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:ALOX15 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23124025 IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6 IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6. References_end </body> </html> </notes> <label text="ALOX15"/> <bbox w="70.0" h="25.0" x="1741.0" y="1859.0"/> </glyph> <glyph class="source and sink" id="s426_sa357" compartmentRef="c8_ca8"> <label text="s426"/> <bbox w="30.0" h="30.0" x="1645.0" y="1495.0"/> </glyph> <glyph class="macromolecule" id="s68_sa46" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="80.0" h="40.0" x="1130.0" y="1940.0"/> <glyph class="state variable" id="_a1e0e71a-5bf6-46d9-abb5-6921d67ed1da"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1122.5" y="1954.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s11_sa9" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated. PMID:10347215 Only JAK1/STAT3 pathway (but not TYK) plays role in anti-inflammatory action of IL10 in macrophages. PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Stat3 activation (tyr 705) by IL-4 requires Jak1 kinase in monocytes PMID:15218058 Stat3 binds ILR1N promoter and upregulates expression of IL1RN downstream of IL10 PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:23454751 MDSC showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3. PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. PMID:19380816 MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). STAT3 mediates the function of MDSCs by regulating NADPH oxidase (NOX2) expression In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:18776941 Expression of VEGF and bFGF, but also IL-1β, MMP9, CCL2, and CXCL2 is STAT3-dependent in myeloid cells. References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="80.0" h="40.0" x="1130.0" y="1860.0"/> <glyph class="state variable" id="_80e77202-7784-4226-9702-88eddd2ea1cd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1125.0" y="1874.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s422_sa348" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="650.0" y="1880.0"/> </glyph> <glyph class="macromolecule" id="s411_sa341" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="IRS2"/> <bbox w="80.0" h="40.0" x="666.5" y="2094.0"/> <glyph class="state variable" id="_43537d15-6e87-401a-a121-3b1aa0ca59ec"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="659.0" y="2109.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s409_sa339" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="IRS2"/> <bbox w="80.0" h="40.0" x="670.0" y="2015.0"/> <glyph class="state variable" id="_daa0cd84-e18a-443f-8854-094663cef023"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="665.0" y="2030.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s347_sa276" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="90.0" h="25.0" x="1345.0" y="1587.5"/> <glyph class="unit of information" id="_832d86b7-e907-46ab-a09c-f0799e20a0ee"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1380.0" y="1582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s346_sa275" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="70.0" h="25.0" x="1245.0" y="1587.5"/> </glyph> <glyph class="macromolecule" id="s311_sa244"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="40.0" y="1515.0"/> </glyph> <glyph class="macromolecule" id="s309_sa240" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="80.0" h="40.0" x="1275.0" y="2204.5"/> <glyph class="state variable" id="_61f7383f-398b-431b-abb9-1f863da880b3"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1267.5" y="2219.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s308_sa239" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="80.0" h="40.0" x="1076.25" y="2206.5"/> <glyph class="state variable" id="_a0251933-2c89-4aae-b302-5b6b19dc0801"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1071.25" y="2221.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s240_sa218" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end </body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="170.0" y="1870.0"/> <glyph class="unit of information" id="_aeab2af9-445d-4fcb-a2ec-7d7dc7a3299a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="187.5" y="1865.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s164_sa136" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 IL10 inhibits miR155 expression via STAT3. 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="70.0" h="25.0" x="1255.0" y="1497.5"/> </glyph> <glyph class="nucleic acid feature" id="s162_sa134" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="90.0" h="25.0" x="2785.0" y="1657.5"/> <glyph class="unit of information" id="_5f3bee34-37db-4124-ad23-3dad68b25860"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2820.0" y="1652.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s161_sa133" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="70.0" h="25.0" x="2795.0" y="1590.5"/> </glyph> <glyph class="macromolecule" id="s122_sa96" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="170.0" y="2000.0"/> <glyph class="state variable" id="_ddfc3a6c-f33d-4b9a-a5cb-c026c10371cc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="245.0" y="2034.3893"/> </glyph> <glyph class="unit of information" id="_5932e53a-8de6-4966-9828-6800cddebf29"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="187.5" y="1995.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s121_sa95" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12907458, PMID:12193690 IL10 upregulates expression of IL4RA in STAT3 dependent manner. PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="90.0" h="25.0" x="1075.0" y="2127.5"/> <glyph class="unit of information" id="_093ea3ea-6197-42b4-950c-495ba424a18f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1110.0" y="2122.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s120_sa94" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12907458, PMID:12193690 IL10 upregulates expression of IL4RA in STAT3 dependent manner. PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. References_end </body> </html> </notes> <label text="IL4R"/> <bbox w="70.0" h="25.0" x="1205.0" y="2127.5"/> </glyph> <glyph class="nucleic acid feature" id="s82_sa59" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SOCS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12907458 IL10 induces SOCS3 expression in STAT3 dependent manner. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="90.0" h="25.0" x="3255.0" y="807.5"/> <glyph class="unit of information" id="_5e4dd166-6a7a-416f-933a-891bf8e6f26a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3290.0" y="802.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s81_sa58" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SOCS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12907458, PMID:16713974 IL10 induces SOCS3 expression in STAT3 dependent manner. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="70.0" h="25.0" x="3265.0" y="887.5"/> </glyph> <glyph class="nucleic acid feature" id="s74_sa51" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="150.5" h="48.5" x="1272.875" y="3019.625"/> <glyph class="unit of information" id="_eb6c0b9d-262c-4dd9-9578-fd6373a7d444"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1338.125" y="3014.625"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s73_sa50" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:20547845 TLR4 signaling downstream of HMGB1 induces secretion of IL10. PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via PMID:15749884 c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. AP1. PMID:25164013 HMGB1 activates MDSCs via the NF-κB pathway It increases MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="118.75" h="42.25" x="1286.875" y="2923.875"/> </glyph> <glyph class="macromolecule" id="s234_sa49" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="126.25" h="72.25" x="1286.875" y="3123.875"/> </glyph> <glyph class="nucleic acid feature" id="s15_sa13" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="90.0" h="25.0" x="1735.5" y="1612.0"/> <glyph class="unit of information" id="_258cddc4-50f9-4d05-b8a5-52124362f248"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1770.5" y="1607.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s14_sa12" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="70.0" h="25.0" x="1744.5" y="1528.0"/> </glyph> <glyph class="macromolecule" id="s13_sa11" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BCL3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A, IL1B,TNF and positively regulates IL-10 expression. BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. References_end </body> </html> </notes> <label text="BCL3"/> <bbox w="80.0" h="40.0" x="1860.0" y="1600.0"/> </glyph> <glyph class="macromolecule" id="s236_sa5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="390.0" y="1115.0"/> </glyph> <glyph class="complex" id="s996_csa76" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LGALS3:SLC3A2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98) References_end </body> </html> </notes> <label text="s996"/> <bbox w="100.0" h="150.0" x="1600.0" y="740.0"/> <glyph class="macromolecule" id="s998_sa904"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="1610.0" y="760.0"/> </glyph> <glyph class="macromolecule" id="s997_sa903"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SLC3A2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98). References_end </body> </html> </notes> <label text="SLC3A2"/> <bbox w="80.0" h="50.0" x="1610.0" y="815.0"/> <glyph class="unit of information" id="_7152b779-7d3d-4a5e-b214-9bc307a7052e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1627.5" y="810.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s959_csa68" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GRB2:IRS2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19109239 Activated IRS2 interacts with Grb2 and activates PI3K signaling downstream of IL4.. References_end </body> </html> </notes> <label text="IRS2/GRB2"/> <bbox w="100.0" h="120.0" x="900.0" y="2010.0"/> <glyph class="macromolecule" id="s961_sa865"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. PMID:19109239 IL4 induces he tyrosine phosphorylation of IRS-2 via Type I IL-4 Receptors. Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="IRS2"/> <bbox w="80.0" h="40.0" x="910.0" y="2060.0"/> <glyph class="state variable" id="_2ea7a033-bf81-465d-a529-c99e2a61f3cc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="902.5" y="2075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s960_sa864"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:GRB2 Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:19109239 Activated IRS2 interacts with Grb2 and activates downstrean PI3K signalin. References_end </body> </html> </notes> <label text="GRB2"/> <bbox w="80.0" h="40.0" x="910.0" y="2020.0"/> </glyph> </glyph> <glyph class="complex" id="s852_csa63" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TGFB1:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12809600 A TGFB ligand initiates signaling by binding to and bringing together type I and type II receptor serine/threonine kinases on the cell surface. References_end </body> </html> </notes> <label text="s852"/> <bbox w="200.0" h="120.0" x="1330.0" y="840.0"/> <glyph class="macromolecule" id="s855_sa754"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TGFB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFB1 participates in M2 activation. PMID:7594497 TGFB1 upregulates IL10 expression in macrophages. TGFB1 and IL10 dowregulate expression of TNF. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling PMID:20644162 Cytokine-induced CD33+ human MDSCs have upregulated iNOS, TGFβ, VEGF. PMID:19109155 MDSC inhibit cytotoxicity, NKG2D expression, and IFN-gamma production of NK cells both in vitro and in vivo. Membrane-bound TGF-beta1 on MDSC is responsible for MDSC-mediated suppression of NK cells. References_end </body> </html> </notes> <label text="TGFB1"/> <bbox w="80.0" h="40.0" x="1440.0" y="860.0"/> </glyph> <glyph class="macromolecule" id="s854_sa753"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TGFBR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12809600 A TGFB ligand initiates signaling by binding to and bringing together type I and type II receptor serine/threonine kinases on the cell surface. References_end </body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="1440.0" y="905.0"/> <glyph class="unit of information" id="_a15cc03e-eac0-4cfc-a944-7332fb9604bb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1457.5" y="900.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s853_sa752"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="1350.0" y="905.0"/> <glyph class="unit of information" id="_6b625208-00db-4d9a-84e2-585c62072ebe"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1367.5" y="900.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s470_csa34" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PPARG:STAT6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:17681149 STAT6, by interacting with PPARγ, facilitates and is required for efficient endogenous PPARγ binding. STAT6 and PPARγ together upregulate CD36 transcription. References_end </body> </html> </notes> <label text="STAT6/PPARG"/> <bbox w="100.0" h="120.0" x="2075.0" y="2158.5"/> <glyph class="macromolecule" id="s472_sa399"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PPARG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:NO_ROS_PRODUCTION MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17681149 PPARG upregulates expression of M2 markers CD163 and MRC1 downstream of IL4. References_end </body> </html> </notes> <label text="PPARG"/> <bbox w="80.0" h="40.0" x="2085.0" y="2218.5"/> </glyph> <glyph class="macromolecule" id="s471_sa398"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAT6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. PMID:23124025 Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:14610620 When the type I or type II IL-4R is dimerized, JAKs associated with the receptor components phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain [50]. This phosphorylation recruits Stat6, which is then also phosphorylated. PhosphoStat6 molecules dimerize and migrate to the nucleus to bind to certain promoters. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:15634881 STAT6-deficient mice produce M1 macrophages. STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO in MDSC. References_end </body> </html> </notes> <label text="STAT6"/> <bbox w="80.0" h="40.0" x="2083.0" y="2165.5"/> <glyph class="state variable" id="_b0acfc4a-6997-4585-941e-e995f5a07f7e"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2075.5" y="2180.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s171_csa20" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR155:SHIP1* Identifiers_end Maps_Modules_begin: MODULE: Maps_Modules_end References_begin: MACROPHAGE PMID:20435894 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. References_end </body> </html> </notes> <label text="SHIP/MIR155"/> <bbox w="108.0" h="87.0" x="2886.0" y="1656.5"/> <glyph class="nucleic acid feature" id="s173_sa143"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:INPP5D Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="90.0" h="25.0" x="2895.5" y="1690.5"/> <glyph class="unit of information" id="_86bc528c-38bd-4270-a45f-5eba45b93712"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2930.5" y="1685.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s172_sa142"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 IL10 inhibits miR155 expression via STAT3. 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="2897.5" y="1662.5"/> <glyph class="unit of information" id="_442a4cae-06c9-44ad-a06a-956943272e46"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2927.5" y="1657.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s622_csa33" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL13RA1:IL4:IL4R:JAK1:JAK2:TYK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID:12223527 Type II IL-4 receptors associates with Jak1,JAK2 and TYK2 PMID:23124025 IL4 binding induces Jak1 phosphorylation (but not Jak2, JAK3, or TYK2). References_end </body> </html> </notes> <label text="IL4/Receptor-TYPE_2"/> <bbox w="284.0" h="173.0" x="138.0" y="2118.5"/> <glyph class="macromolecule" id="s436_sa364"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TYK2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODUULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="298.875" y="2167.25"/> <glyph class="state variable" id="_ca1e817b-562a-4aa6-a0f5-75ad80e5a878"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="293.875" y="2182.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s435_sa363"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="300.0" y="2125.0"/> <glyph class="state variable" id="_1d80113b-0994-480e-9e93-e3414e867a41"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="292.5" y="2140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s437_sa362"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="290.0" y="2215.0"/> <glyph class="state variable" id="_00998b53-68fa-4e7d-b26d-1a9e301bfe94"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="285.0" y="2230.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s431_sa361"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="138.5" y="2171.0"/> </glyph> <glyph class="macromolecule" id="s434_sa360"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="80.0" h="50.0" x="218.85715" y="2170.6428"/> <glyph class="state variable" id="_a313a730-202b-4889-9bda-6a59b6dce5d1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="293.85715" y="2204.3994"/> </glyph> <glyph class="unit of information" id="_26c983f9-95c6-450b-9ff6-b3cbe4906e94"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="236.35715" y="2165.6428"/> </glyph> </glyph> <glyph class="macromolecule" id="s433_sa359"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="218.85715" y="2131.6428"/> <glyph class="state variable" id="_61a99c05-ad0b-4177-b9a4-bc7e6e03cb40"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="293.85715" y="2166.032"/> </glyph> <glyph class="unit of information" id="_71f84d81-a4a9-41fb-9ab8-02816c9b9c30"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="236.35715" y="2126.6428"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s242_csa25" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL2RG:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end </body> </html> </notes> <label text="IL4_receptor_TYPE1"/> <bbox w="104.0" h="133.0" x="278.0" y="1898.5"/> <glyph class="macromolecule" id="s329_sa232"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="291.85715" y="1948.6428"/> <glyph class="state variable" id="_f8b2546c-8f09-40eb-84e1-85479d33bbf1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="366.85715" y="1983.0321"/> </glyph> <glyph class="unit of information" id="_675ea189-2081-491c-ab0d-4ec18c92ef4c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="309.35715" y="1943.6428"/> </glyph> </glyph> <glyph class="macromolecule" id="s328_sa231"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end </body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="291.85715" y="1907.6428"/> <glyph class="unit of information" id="_4ffe8913-0f4a-4e8f-bffa-c625d13967c1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="309.35715" y="1902.6428"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s184_csa2" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL10RA:IL10RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10R contains two subunits IL1ORA and IL10RB PMID:‭15833879 ‭Anti IL-10 receptor–specific antibody switched TAMs from an M2 to an M1 macrophage–like phenotype. References_end </body> </html> </notes> <label text="IL10R"/> <bbox w="179.0" h="107.0" x="490.5" y="1421.5"/> <glyph class="macromolecule" id="s42_sa7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="583.5" y="1452.5"/> <glyph class="unit of information" id="_7ee423fc-3f27-4c4a-9b47-9cfe9e7f3c52"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="601.0" y="1447.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s41_sa6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="499.5" y="1454.5"/> <glyph class="state variable" id="_5b7ffe08-19ed-4293-a1b6-bf62462e7dbb"> <state value="" variable="Y496"/> <bbox w="30.0" h="10.0" x="484.5" y="1456.3364"/> </glyph> <glyph class="state variable" id="_8945ff9a-7f07-46a0-bbcc-d36263dd1d4c"> <state value="" variable="Y446"/> <bbox w="30.0" h="10.0" x="526.6581" y="1499.5"/> </glyph> <glyph class="unit of information" id="_75bab0a6-5fb7-43a5-b22d-4acfbdf99fb2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="517.0" y="1449.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s348_csa30" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL13RA1:MIR155 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="IL13RA1/MIR155"/> <bbox w="114.0" h="102.0" x="1483.0" y="1519.0"/> <glyph class="nucleic acid feature" id="s350_sa278"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MIR155 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20435894 IL10 inhibits miR155 expression via STAT3. 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="1499.375" y="1538.25"/> <glyph class="unit of information" id="_081aaf99-4e93-41b1-8b2d-bf089fba01aa"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1529.375" y="1533.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s349_sa277"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL13RA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21097505 miR-155 Directly Targets IL13RA1, reduces the IL-13- and IL-4-dependent Phosphorylation of STAT6 in Human Macrophages and downregulates IL-13 dependent GENES References_end </body> </html> </notes> <label text="IL13RA1"/> <bbox w="90.0" h="25.0" x="1499.375" y="1562.25"/> <glyph class="unit of information" id="_94115cef-64d9-4852-a465-c017256960c4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1534.375" y="1557.25"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s301_csa10" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL10:IL10RA:IL10RB:JAK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="IL10R/IL10/JAK1"/> <bbox w="179.0" h="177.0" x="770.5" y="1081.5"/> <glyph class="macromolecule" id="s304_sa39"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="783.5" y="1086.0"/> </glyph> <glyph class="macromolecule" id="s303_sa38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="860.5" y="1133.5"/> <glyph class="unit of information" id="_5f9b0949-33d5-4cf0-9443-5521f9a51af4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="878.0" y="1128.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s189_sa37"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="784.5" y="1133.5"/> <glyph class="state variable" id="_d262a51b-8ad6-4f74-8770-5f5a2a8311cb"> <state value="" variable="Y496"/> <bbox w="30.0" h="10.0" x="769.5" y="1135.3364"/> </glyph> <glyph class="state variable" id="_82c30df7-e251-4853-b721-02fb9130a76d"> <state value="" variable="Y446"/> <bbox w="30.0" h="10.0" x="811.6581" y="1178.5"/> </glyph> <glyph class="unit of information" id="_d1ed5728-7b35-43a5-a94b-4badfee07658"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="802.0" y="1128.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s302_sa36"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="786.5" y="1192.0"/> <glyph class="state variable" id="_f50565ad-2cac-47b7-97f3-688701e11b1a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="779.0" y="1207.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1373_sa1063"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TYK2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODUULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="860.0" y="1190.0"/> <glyph class="state variable" id="_e01eec6b-b348-45df-8a9a-152a77fb4c97"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="852.5" y="1205.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s331_csa27" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL2RG:IL4:IL4R:JAK1:JAK2:JAK3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID:20510870 Type I IL-4 receptors is assosiated with Jak1,JAK2 and JAK3. IL-4Ra associates with JAK1, JAK2 and gammaC with JAK3. PMID:23124025 IL4 binding induces Jak1 phosphorylation (but not Jak2, JAK3, or TYK2). References_end </body> </html> </notes> <label text="IL4_receptor_TYPE1"/> <bbox w="269.0" h="151.0" x="231.0" y="1654.0"/> <glyph class="macromolecule" id="s421_sa347"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="400.0" y="1745.0"/> <glyph class="state variable" id="_fcf03d97-8b47-4111-923c-8af63707a197"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="395.0" y="1760.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s420_sa315"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="402.5" y="1706.5"/> <glyph class="state variable" id="_155d9792-9fe5-4e03-b851-d15886f4b1b0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="395.0" y="1721.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s381_sa314"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="JAK3"/> <bbox w="80.0" h="40.0" x="401.5" y="1667.5"/> </glyph> <glyph class="macromolecule" id="s330_sa267"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12401408 IL4 is assosiated with M2 polarization of macrophages PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID:12496409 Arg1 is up-regulated in MDSC by IL-4. Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="241.0" y="1705.5"/> </glyph> <glyph class="macromolecule" id="s333_sa265"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL4R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α ARG1, TGFB, COX2 expression is downregulated in IL4R-/- MDSC (probably via STAT3 and MYC). </body> </html> </notes> <label text="IL4R"/> <bbox w="80.0" h="50.0" x="321.85715" y="1707.1428"/> <glyph class="state variable" id="_722f79aa-84fa-44b7-a38b-53b03bddcb72"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="396.85715" y="1741.5321"/> </glyph> <glyph class="unit of information" id="_10d5bdad-4fca-4b02-9970-db6ea375c1e1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="339.35715" y="1702.1428"/> </glyph> </glyph> <glyph class="macromolecule" id="s332_sa264"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL2RG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23124025, PMID:20856220 In human monocytes, IL-4 mediates its effect through the type I IL-4R, composed of the IL-4Rα and common gamma-chain (IL-2Rγ); And, probably through type II IL-4Ris composed of the IL-4Ra chain and IL-13Ra1 References_end </body> </html> </notes> <label text="IL2RG"/> <bbox w="80.0" h="50.0" x="321.85715" y="1668.1428"/> <glyph class="unit of information" id="_6d67c5cd-ddd6-421f-ae4a-c087f43f929f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="339.35715" y="1663.1428"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s185_csa9" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL10:IL10RA:IL10RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. PMID:‭15833879 ‭Anti IL-10 receptor–specific antibody switched TAMs from an M2 to an M1 macrophage–like phenotype. References_end </body> </html> </notes> <label text="IL10R/IL10"/> <bbox w="180.0" h="131.0" x="590.0" y="1259.5"/> <glyph class="macromolecule" id="s50_sa35"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="600.0" y="1271.0"/> </glyph> <glyph class="macromolecule" id="s49_sa34"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="681.0" y="1311.5"/> <glyph class="unit of information" id="_29bead87-a1e8-4d33-bc44-3758f123b7b5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="698.5" y="1306.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s48_sa33"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="605.0" y="1311.5"/> <glyph class="state variable" id="_48ed3f08-7d1f-434f-9f14-76f22b085468"> <state value="" variable="Y496"/> <bbox w="30.0" h="10.0" x="590.0" y="1313.3364"/> </glyph> <glyph class="state variable" id="_012e99f3-bf66-4e3a-8f7c-85c788526a6d"> <state value="" variable="Y446"/> <bbox w="30.0" h="10.0" x="632.1581" y="1356.5"/> </glyph> <glyph class="unit of information" id="_9ce50312-3e5c-41a9-a098-5a55274c8c6b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="622.5" y="1306.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s287_csa11" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL10:IL10RA:IL10RB:JAK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 References_end </body> </html> </notes> <label text="IL10R/IL10/JAK1"/> <bbox w="179.0" h="177.0" x="960.5" y="1021.5"/> <glyph class="macromolecule" id="s288_sa45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="970.0" y="1140.0"/> <glyph class="state variable" id="_6e32a5bc-8552-4daa-b0cb-39b8844d055f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="962.5" y="1155.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s290_sa42"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385 IL10 is immunosuppressive cytokine. PMID:10623821, PMID:10623821 IL10‭ ‬ expression in macrophages is assosiated with TAM (M2) phenotype. PMID:10542212 IL10‭ ‬ promotes M2‭ ‬phenotype of macrophages trough suppression of‭ ‬NFkB signaling and inhibition of synthesis of pro-inflammatory cytokines. PMID:11875494 IL10 stimulates HO1 expression via MAPK p38 stimulation. PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. PMID:PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="973.5" y="1026.0"/> </glyph> <glyph class="macromolecule" id="s289_sa41"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RB"/> <bbox w="80.0" h="50.0" x="1050.5" y="1073.5"/> <glyph class="unit of information" id="_0bd2304a-0239-4fdc-9a72-08ccf1e788d9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1068.0" y="1068.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s64_sa40"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL10RA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. References_end </body> </html> </notes> <label text="IL10RA"/> <bbox w="80.0" h="50.0" x="974.5" y="1073.5"/> <glyph class="state variable" id="_ee0885b4-85c0-4aa1-8846-745cfb2b1237"> <state value="P" variable="Y496"/> <bbox w="35.0" h="10.0" x="957.0" y="1075.3364"/> </glyph> <glyph class="state variable" id="_31ff8d62-f012-4c32-929b-f53c5295ac45"> <state value="P" variable="Y446"/> <bbox w="35.0" h="10.0" x="999.1581" y="1118.5"/> </glyph> <glyph class="unit of information" id="_3a92d63e-b246-47cb-ba2a-abfa9b0479de"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="992.0" y="1068.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1372_sa1062"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TYK2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODUULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="1050.0" y="1140.0"/> <glyph class="state variable" id="_5da5abbd-7d7c-4385-96de-e18905be87fd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1042.5" y="1155.0"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s967_sa871" compartmentRef="c8_ca8"> <label text="s967"/> <bbox w="30.0" h="30.0" x="3065.0" y="1910.0"/> </glyph> <glyph class="macromolecule" id="s963_sa868" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. References_end </body> </html> </notes> <label text="p110*"/> <bbox w="80.0" h="40.0" x="2660.0" y="1885.0"/> </glyph> <glyph class="macromolecule" id="s962_sa867" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PIK3R1 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 GENECARDS:PIK3R1 HUGO:PIK3R2 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 GENECARDS:PIK3R2 HUGO:PIK3R3 HGNC:8981 ENTREZ:8503 UNIPROT:Q92569 GENECARDS:PIK3R3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61192 KEGG:5295 ATLASONC:PIK3R1ID41717ch5q13 WIKI:PIK3R1 REACTOME:61194 KEGG:5296 ATLASONC:GC_PIK3R2 WIKI:PIK3R2 REACTOME:61182 KEGG:8503 ATLASONC:GC_PIK3R3 WIKI:PIK3R3 PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:19109239 Activated IRS2 interacts with Grb2 and activates PI3K signaling downstream of IL4. PMID:18250477 Galectin 3 mediate alternative activation of macrophages via activation of PI3K signaling and AKT posphorylation. And regulates expression of MRC1 probably via PI3K. References_end </body> </html> </notes> <label text="p85*"/> <clone/> <bbox w="80.0" h="40.0" x="2660.0" y="1805.0"/> </glyph> <glyph class="macromolecule" id="s962_sa866" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PIK3R1 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 GENECARDS:PIK3R1 HUGO:PIK3R2 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 GENECARDS:PIK3R2 HUGO:PIK3R3 HGNC:8981 ENTREZ:8503 UNIPROT:Q92569 GENECARDS:PIK3R3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61192 KEGG:5295 ATLASONC:PIK3R1ID41717ch5q13 WIKI:PIK3R1 REACTOME:61194 KEGG:5296 ATLASONC:GC_PIK3R2 WIKI:PIK3R2 REACTOME:61182 KEGG:8503 ATLASONC:GC_PIK3R3 WIKI:PIK3R3 PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:19109239 Activated IRS2 interacts with Grb2 and activates PI3K signaling downstream of IL4. PMID:18250477 Galectin 3 mediate alternative activation of macrophages via activation of PI3K signaling and AKT posphorylation. And regulates expression of MRC1 probably via PI3K. References_end </body> </html> </notes> <label text="p85*"/> <clone/> <bbox w="80.0" h="40.0" x="2660.0" y="1725.0"/> </glyph> <glyph class="macromolecule" id="s864_sa764" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF5 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as IRF5 PMID:21240265 High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. References_end </body> </html> </notes> <label text="IRF5"/> <bbox w="80.0" h="40.0" x="4415.0" y="1973.5"/> </glyph> <glyph class="nucleic acid feature" id="s863_sa763" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF5 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as IRF5 References_end </body> </html> </notes> <label text="IRF5"/> <bbox w="90.0" h="25.0" x="4405.0" y="1927.5"/> <glyph class="unit of information" id="_f9a8acfe-4017-4df9-b6c4-84349118dfe4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4440.0" y="1922.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s862_sa762" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF5 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23390297 MIF inhitits expression of M1 markers such as IRF5 PMID:21240265 GM-CSF upregulates IRF5 expression. References_end </body> </html> </notes> <label text="IRF5"/> <bbox w="70.0" h="25.0" x="4420.0" y="1871.0"/> </glyph> <glyph class="nucleic acid feature" id="s858_sa757" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. References_end </body> </html> </notes> <label text="IRAK3"/> <bbox w="90.0" h="25.0" x="4495.0" y="1192.5"/> <glyph class="unit of information" id="_45cc868d-ff99-44d8-bb0e-bd834395bf20"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4530.0" y="1187.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s857_sa756" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. PMID:21278795 TGFB-induced IRAK3 (IRAK-M) expression in tumor-associated macrophages and inhibit TLR-dependent signaling References_end </body> </html> </notes> <label text="IRAK3"/> <bbox w="70.0" h="25.0" x="4405.0" y="1192.5"/> </glyph> <glyph class="nucleic acid feature" id="s845_sa744" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. TNF inhibit CCR2 expression in tumor associated macrophages. References_end </body> </html> </notes> <label text="CCR2"/> <bbox w="90.0" h="25.0" x="2580.0" y="821.0"/> <glyph class="unit of information" id="_d24798fa-e043-4ac6-9708-0fb5f51d88ed"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2615.0" y="816.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s844_sa743" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CCR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. 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PMID:16007092 GSK3B inhibits CREB1 interaction with CBP and inhibits CREB1 dependent IL10 expression. CREB1/CBP complex formation prevents binding CBP to RELA (p65) and inhibits downstream NF-kB signaling. 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References_end </body> </html> </notes> <label text="RELA"/> <bbox w="70.0" h="25.0" x="3300.0" y="1376.0"/> </glyph> <glyph class="nucleic acid feature" id="s726_sa650" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="70.0" h="25.0" x="4655.0" y="1017.5"/> </glyph> <glyph class="nucleic acid feature" id="s725_sa649" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LY96 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="90.0" h="25.0" x="4565.0" y="947.5"/> <glyph class="unit of information" id="_5e088513-6737-4445-9c97-8715b35f3acb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4600.0" y="942.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s724_sa648" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LY96 MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="70.0" h="25.0" x="4555.0" y="997.5"/> </glyph> <glyph class="nucleic acid feature" id="s696_sa621" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TLR4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313, PMID:11672593, PMID:12032143, PMID:12811837. INFG upregulates mRNA level and surface expression of TLR4 and TLR2. 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PMID:11888900, PMID:20644254 HIF2A induces tumor growth and angiogenesis. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. 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PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. References_end </body> </html> </notes> <label text="HIF2A*"/> <clone/> <bbox w="80.0" h="40.0" x="2860.0" y="1130.0"/> </glyph> <glyph class="macromolecule" id="s557_sa507" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HIF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:24006507 HIF1A expression is assotiated with classical activation of macrophages PMID:20427344 HIF1 expression is assotiated with classical activation of macrophages HIF1A upregulates expression of: TNF, IL6, HIF1A downregulates expression of M2 markers CD206 and STAB1. PMID_24006507 IL4 downregulates HIF1a translation. PMID:21765015 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth References_end </body> </html> </notes> <label text="HIF1A"/> <clone/> <bbox w="80.0" h="40.0" x="3180.0" y="1120.0"/> </glyph> <glyph class="macromolecule" id="s557_sa478" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HIF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:24006507 HIF1A expression is assotiated with classical activation of macrophages PMID:20427344 HIF1 expression is assotiated with classical activation of macrophages HIF1A upregulates expression of: TNF, IL6, HIF1A downregulates expression of M2 markers CD206 and STAB1. PMID_24006507 IL4 downregulates HIF1a translation. PMID:21765015 CSF2 upregulates VEGF expression via HIF1a specific inhibition of PHD2 increases VEGF production HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors. PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. 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References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="70.0" h="25.0" x="2295.0" y="847.5"/> </glyph> <glyph class="nucleic acid feature" id="s577_sa500" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF1R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="70.0" h="25.0" x="2705.0" y="817.5"/> </glyph> <glyph class="nucleic acid feature" id="s576_sa499" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF1R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="90.0" h="25.0" x="2695.0" y="757.5"/> <glyph class="unit of information" id="_fdb15d7e-c9d8-43d2-acd7-b66f676363fc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2730.0" y="752.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s575_sa498" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF1R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="80.0" h="50.0" x="2530.0" y="425.0"/> <glyph class="unit of information" id="_2d18ebc5-306e-4d81-a57f-0ae71422ec10"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2547.5" y="420.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s574_sa497" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:EPAS1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:20194441 IFNG strongly reduced HIF-2A mRNA synthesis. IL4 and IL13 upregulates HIF2a expression, probably via STAT6 pathway. PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors References_end </body> </html> </notes> <label text="HIF2A*"/> <bbox w="70.0" h="25.0" x="2865.0" y="997.5"/> </glyph> <glyph class="nucleic acid feature" id="s573_sa496" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:EPAS1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:16127144 HIF-1A and HIF-2A are up-regulated by human macrophages exposed to hypoxia in vitro and by TAMs in hypoxic/necrotic areas of human tumors References_end </body> </html> </notes> <label text="HIF2A*"/> <bbox w="90.0" h="25.0" x="2855.0" y="1077.5"/> <glyph class="unit of information" id="_71d10d92-847a-4ee9-a165-4bbe4cf7c8b9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2890.0" y="1072.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s572_sa495" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HIF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID_24006507 HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="90.0" h="25.0" x="3175.0" y="1067.5"/> <glyph class="unit of information" id="_21a6656b-73df-4103-b3ef-92ef60492232"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3210.0" y="1062.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s571_sa494" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HIF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:20194441 IFNG enhanced the synthesis of HIF-1A mRNA. PMID:24006507 HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. PMID:22067385 c-MYC is expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1A, and TGFB. References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="70.0" h="25.0" x="3186.0" y="997.5"/> </glyph> <glyph class="nucleic acid feature" id="s561_sa482" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23390297, PMID:22461508, PMID:8195715 MIF is expresed by macrophages References_end </body> </html> </notes> <label text="MIF"/> <bbox w="90.0" h="25.0" x="1565.0" y="3117.5"/> <glyph class="unit of information" id="_2940bc49-214c-47ff-8414-81c7d9248efa"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1600.0" y="3112.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s560_sa481" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23390297, PMID:22461508, PMID:8195715 MIF is expresed by macrophages H2O2 induces MIF expression in macrophages (http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A2803) PMID:8195715 TNF and INFG induce MIF expression in macrophages. PMID_24006507 HIF1a induces MIF expression of macrophages after hypoxia. IL4+IL13 inhibit MIF expression via inhibition of HIF1a expression. References_end </body> </html> </notes> <label text="MIF"/> <bbox w="70.0" h="25.0" x="1577.0" y="3047.5"/> </glyph> <glyph class="macromolecule" id="s559_sa480" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23390297, PMID:22461508, PMID:8195715 MIF is expresed by macrophages PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression and activates tumor invasion. PMID:23390297 MIF inhitits expression of M1 markers such as TNF, IL12p40, COX2, INOS, IRF-5, MHC-II, CD11c, CD80, CD86. MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD206, CD23. References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="1570.0" y="3190.0"/> </glyph> <glyph class="macromolecule" id="s556_sa477" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MRC2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="MRC2"/> <bbox w="80.0" h="40.0" x="2500.0" y="3410.0"/> </glyph> <glyph class="nucleic acid feature" id="s555_sa476" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MRC2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="MRC2"/> <bbox w="90.0" h="25.0" x="2485.0" y="3357.5"/> <glyph class="unit of information" id="_4e7cc7ac-e98d-40f9-9e49-f4151b9b010d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2520.0" y="3352.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s554_sa475" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MRC2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="MRC2"/> <bbox w="70.0" h="25.0" x="2493.0" y="3291.125"/> </glyph> <glyph class="macromolecule" id="s552_sa474" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:AKT1 HUGO:AKT2 HUGO:AKT3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). 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References_end </body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="3185.0" y="2098.5"/> <glyph class="state variable" id="_03eeda64-7b35-497e-9db8-c66c66b63072"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3180.0" y="2113.4683"/> </glyph> </glyph> <glyph class="macromolecule" id="s551_sa472" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. PMID:18250477 LGALS3 participates in M2 activation of macrophages. And vice versa classically activated macrophages down-regulate galectin-3 expression and show reduced galectin-3 expression on the cell surface. IL-4 or IL-13 stimulated the release of galectin-3 into the culture media in both BMDMs and PBMs. An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor CD98. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="80.0" h="40.0" x="1470.0" y="3030.0"/> </glyph> <glyph class="nucleic acid feature" id="s550_sa471" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="90.0" h="25.0" x="1465.0" y="2977.5"/> <glyph class="unit of information" id="_b0fae50c-0ed2-4a14-a6b9-df9c1a5d84a3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1500.0" y="2972.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s549_sa470" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LGALS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:22703233 TGFBR2 upregulates expression of markers M2 activation as ARG1, MCR2 and LGALS3 (galecsin3) and induces AKT activation. References_end </body> </html> </notes> <label text="LGALS3"/> <bbox w="70.0" h="25.0" x="1475.0" y="2927.5"/> </glyph> <glyph class="macromolecule multimer" id="s546_sa467" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="141.5" h="141.5" x="2419.25" y="1719.25"/> <glyph class="unit of information" id="_62d5847e-4201-477f-b81c-c33b18fdbdb2"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2480.0" y="1714.25"/> </glyph> <glyph class="unit of information" id="_ec231f81-749c-445e-95b5-57b88bff4d19"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2465.0" y="1714.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s545_sa466"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:24669294 SCF1 (M-CSF) is assosiated with M2 phenotype of macrophages References_end </body> </html> </notes> <label text="CSF1"/> <bbox w="80.0" h="40.0" x="2570.0" y="190.0"/> </glyph> <glyph class="macromolecule" id="s544_sa464"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24669294 SCF2 (GM-CSF) is assosiated with M1 phenotype of macrophages PMID:12928384 GM-CSF enhances monocyte APC function. GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOalpha. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA. PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. PMID:22698406 Granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="3750.0" y="180.0"/> </glyph> <glyph class="macromolecule" id="s507_sa427" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:KDM6B Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19567879 KDM6B ( Jmjd3) demethylates H3K27me2/3 in promoters of M2 marker genes (ARG1 and probably MRC1) and contributes to maintaining M2 marker genes in a transcriptionally active state. 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PMID: PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. 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PMID: PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. 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TYK2 associated with IL13RA1 participates in signal transduction. 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IL-10 Inhibits TNF translation through SHIP1-mediated Inhibition of MKNK1. 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PMID:21469115 SHIP inhibits PI3K signaling and prevents M2 polarisation downstream of IL4, But IL4 signaling reduces SHIP protein levels and activity via PI3K correlating with M2 marker induction ( activation of arginase protein level and activity and inhibition of NO production). PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. References_end </body> </html> </notes> <label text="SHIP1*"/> <bbox w="80.0" h="40.0" x="3040.0" y="1805.0"/> </glyph> <glyph class="nucleic acid feature" id="s153_sa125" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBID Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="90.0" h="25.0" x="2433.0" y="1509.0"/> <glyph class="unit of information" id="_14766d03-8fba-45f2-bf02-41f2317a4800"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2468.0" y="1504.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s152_sa124" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBID Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="70.0" h="25.0" x="2443.0" y="1455.0"/> </glyph> <glyph class="macromolecule" id="s151_sa123" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBID Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <label text="NFKBID"/> <bbox w="80.0" h="40.0" x="2435.0" y="1558.5"/> </glyph> <glyph class="macromolecule" id="s134_sa106" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAPK11 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 GENECARDS:MAPK11 HUGO:MAPK12 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 GENECARDS:MAPK12 HUGO:MAPK13 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 GENECARDS:MAPK13 HUGO:MAPK14 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 GENECARDS:MAPK14 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 PMID:11875494 IL10-induced p38 phosphorylation. PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. PMID:10925299 IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation downstream of IL13 PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. References_end </body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="3605.0" y="2188.5"/> <glyph class="state variable" id="_cd7874bf-6841-4fd1-b93e-315980c19af7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3597.5" y="2203.4683"/> </glyph> </glyph> <glyph class="macromolecule" id="s133_sa105" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MAPK11 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 GENECARDS:MAPK11 HUGO:MAPK12 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 GENECARDS:MAPK12 HUGO:MAPK13 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 GENECARDS:MAPK13 HUGO:MAPK14 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 GENECARDS:MAPK14 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 PMID:11875494 IL10-induced p38 phosphorylation. PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. PMID:10925299 IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation downstream of IL13 PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. References_end </body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="3605.0" y="2108.5"/> <glyph class="state variable" id="_f000b02d-a847-45a4-9478-9dc88570661a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3600.0" y="2123.4683"/> </glyph> </glyph> <glyph class="macromolecule" id="s113_sa87" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10542212 The primary level of control of NFkB heterodimer is through its interaction with the inhibitorprotein NFKBIA (IkBa). IL10 inhibits TNF-dependent degradation of NFKBIA. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via prevention of degradation of IkBa PMID:17485448, PMID:10542212 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. References_end </body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="3892.5" y="1786.5"/> <glyph class="state variable" id="_8cd5a7b9-12c8-4cf3-a75b-be5ce99de64f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3887.5" y="1801.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s112_sa85" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10542212 The primary level of control of NFkB heterodimer is through its interaction with the inhibitorprotein NFKBIA (IkBa). IL10 inhibits TNF-dependent degradation of NFKBIA. References_end </body> </html> </notes> <label text="NFKBIA"/> <bbox w="90.0" h="25.0" x="3875.0" y="1862.5"/> <glyph class="unit of information" id="_6146865f-cdfe-49c5-a2ec-da3fef004065"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3910.0" y="1857.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s111_sa84" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10542212 The primary level of control of NFkB heterodimer is through its interaction with the inhibitorprotein NFKBIA (IkBa). IL10 inhibits TNF-dependent degradation of NFKBIA. References_end </body> </html> </notes> <label text="NFKBIA"/> <bbox w="70.0" h="25.0" x="3895.0" y="1927.5"/> </glyph> <glyph class="macromolecule" id="s96_sa71" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10542212 The primary level of control of NFkB heterodimer is through its interaction with the inhibitorprotein NFKBIA (IkBa). IL10 inhibits TNF-dependent degradation of NFKBIA. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via prevention of degradation of IkBa PMID:17485448, PMID:10542212 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. References_end </body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="3633.5" y="1717.5"/> <glyph class="state variable" id="_f2209af5-743b-4972-b1f9-ef5646c0d72f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3626.0" y="1732.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s86_sa63" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNIP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. PMID:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 () References_end </body> </html> </notes> <label text="TNIP3"/> <bbox w="80.0" h="40.0" x="3560.0" y="975.0"/> </glyph> <glyph class="nucleic acid feature" id="s85_sa62" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNIP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="TNIP3"/> <bbox w="90.0" h="25.0" x="3415.0" y="987.5"/> <glyph class="unit of information" id="_96583688-a32c-42d6-aa52-2ba7044bef0d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3450.0" y="982.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s84_sa61" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNIP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="TNIP3"/> <bbox w="70.0" h="25.0" x="3428.0" y="933.5"/> </glyph> <glyph class="macromolecule" id="s83_sa60" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SOCS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12754507 IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="80.0" h="40.0" x="3270.0" y="710.0"/> </glyph> <glyph class="macromolecule" id="s29_sa25" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HDAC1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="HDAC1"/> <bbox w="80.0" h="40.0" x="4192.5" y="2125.25"/> </glyph> <glyph class="macromolecule" id="s19_sa15" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation. Ser536 is phoshorylated downstream of RAGE signaling in MDSC. References_end </body> </html> </notes> <label text="RELA"/> <bbox w="130.0" h="90.0" x="3275.0" y="1525.0"/> <glyph class="state variable" id="_9ddd3c7a-b582-4399-a3a7-d615580e7b89"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3270.0" y="1565.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s18_sa14" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="140.0" h="90.0" x="2865.0" y="1493.5"/> <glyph class="unit of information" id="_9c55fe55-34bd-4ac4-8c4b-3f98817ee994"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2910.0" y="1488.5"/> </glyph> </glyph> <glyph class="complex" id="s964_csa69" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:p110*:p85* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11687500 PI3K converts phosphatidylinositol 4,5-biphosphate ( PI(4,5)P 2 ) to phosphatidylinositol 3,4,5-triphosphate ( PI(3,4,5)P 3 ), which is secondary messenger involved the in regulation of various process . PI(3,4,5)P 3 associates with the inner lipid bilayer of the plasma membrane and promotesthe recruitment of proteins with pleckstrin homology (PH) domains such as AKT and PDK. Upon binding to the membrane AKT and PDK became active. Notably, translocation of AKT to the plasma membrane also facilitates its phosphorylation by PDK. References_end </body> </html> </notes> <label text="PI3K complex"/> <bbox w="100.0" h="120.0" x="2790.0" y="1805.0"/> <glyph class="macromolecule" id="s966_sa870"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PIK3R1 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 GENECARDS:PIK3R1 HUGO:PIK3R2 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 GENECARDS:PIK3R2 HUGO:PIK3R3 HGNC:8981 ENTREZ:8503 UNIPROT:Q92569 GENECARDS:PIK3R3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61192 KEGG:5295 ATLASONC:PIK3R1ID41717ch5q13 WIKI:PIK3R1 REACTOME:61194 KEGG:5296 ATLASONC:GC_PIK3R2 WIKI:PIK3R2 REACTOME:61182 KEGG:8503 ATLASONC:GC_PIK3R3 WIKI:PIK3R3 PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:19109239 Activated IRS2 interacts with Grb2 and activates PI3K signaling downstream of IL4. PMID:18250477 Galectin 3 mediate alternative activation of macrophages via activation of PI3K signaling and AKT posphorylation. And regulates expression of MRC1 probably via PI3K. References_end </body> </html> </notes> <label text="p85*"/> <bbox w="80.0" h="40.0" x="2800.0" y="1815.0"/> </glyph> <glyph class="macromolecule" id="s965_sa869"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:PIK3CA HGNC:8975 ENTREZ:5290 UNIPROT:P42336 GENECARDS:PIK3CA HUGO:PIK3CB HGNC:8976 ENTREZ:5291 UNIPROT:P42338 GENECARDS:PIK3CB HUGO:PIK3CD HGNC:8977 ENTREZ:5293 UNIPROT:O00329 GENECARDS:PIK3CD HUGO:PIK3CG HGNC:8978 ENTREZ:5294 UNIPROT:P48736 GENECARDS:PIK3CG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. References_end </body> </html> </notes> <label text="p110*"/> <bbox w="80.0" h="40.0" x="2800.0" y="1865.0"/> </glyph> </glyph> <glyph class="complex" id="s903_csa67" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CBP*:CREB1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16007092 GSK3B inhibits CREB1 interaction with CBP and inhibits CREB1 dependent IL10 expression. CREB1/CBP complex formation prevents binding CBP to RELA (p65) and inhibits downstream NF-kB signaling. References_end </body> </html> </notes> <label text="s903"/> <bbox w="105.0" h="150.0" x="4187.5" y="1635.0"/> <glyph class="macromolecule" id="s907_sa806"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CREB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production. TLR activation of CREB by phosphorylation of serine-133 is dependent on p38. References_end </body> </html> </notes> <label text="CREB1"/> <bbox w="80.0" h="40.0" x="4202.5" y="1645.0"/> <glyph class="state variable" id="_ed5eef9c-415d-4aaf-9c7a-66716df6b646"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4195.0" y="1660.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s904_sa803"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CREBBP Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19879327 STAT1 is acetylated by CBP at the lysine residues K410 and K413. PMID:16007092 GSK3B induces RELA (p65) interaction with CBP and activates downstream NF-kB signaling end expression of proinflammatory cytokines. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. PMID:12417340 IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator in macrophages. References_end </body> </html> </notes> <label text="CBP*"/> <bbox w="80.0" h="40.0" x="4202.5" y="1695.0"/> </glyph> </glyph> <glyph class="complex" id="s902_csa66" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CBP*:RELA Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16007092 GSK3B induces RELA (p65) interaction with CBP and activates downstream NF-kB signaling end expression of proinflammatory cytokines. References_end </body> </html> </notes> <label text="s902"/> <bbox w="100.0" h="150.0" x="4050.0" y="1645.0"/> <glyph class="macromolecule" id="s906_sa805"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation. Ser536 is phoshorylated downstream of RAGE signaling in MDSC. References_end </body> </html> </notes> <label text="RELA"/> <bbox w="80.125" h="49.625" x="4059.9375" y="1650.1875"/> <glyph class="state variable" id="_dd7ce429-a921-47ed-893f-0183c8f9a514"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4054.9375" y="1670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s905_sa804"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CREBBP Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19879327 STAT1 is acetylated by CBP at the lysine residues K410 and K413. PMID:16007092 GSK3B induces RELA (p65) interaction with CBP and activates downstream NF-kB signaling end expression of proinflammatory cytokines. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. PMID:12417340 IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator in macrophages. References_end </body> </html> </notes> <label text="CBP*"/> <bbox w="80.0" h="40.0" x="4060.0" y="1705.0"/> </glyph> </glyph> <glyph class="complex" id="s747_csa55" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PDPK1:PIP3* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). References_end </body> </html> </notes> <label text="s747"/> <bbox w="100.0" h="120.0" x="3065.0" y="1988.5"/> <glyph class="simple chemical" id="s749_sa677"> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="3080.0" y="2006.0"/> </glyph> <glyph class="macromolecule" id="s748_sa676"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). References_end </body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="3075.0" y="2038.5"/> </glyph> </glyph> <glyph class="complex" id="s128_csa17" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL6R:gp130* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="123.25" h="133.625" x="3166.75" y="380.0"/> <glyph class="macromolecule" id="s131_sa101"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="3190.0" y="435.0"/> <glyph class="state variable" id="_0f81bcdb-3470-4b2f-904a-cc60332068e1"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="3252.5" y="432.54102"/> </glyph> <glyph class="unit of information" id="_dbfc8424-772c-4cac-9790-9e1c2616df96"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3207.5" y="430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s130_sa100"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="3190.0" y="395.0"/> <glyph class="unit of information" id="_e79b6acc-c3cb-42d1-94fd-1144ddf6710c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3207.5" y="390.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s651_csa48" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MAP3K7:TAB2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1. References_end </body> </html> </notes> <label text="s651"/> <bbox w="100.0" h="130.0" x="3890.0" y="1155.0"/> <glyph class="macromolecule" id="s646_sa577"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MAP3K7 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="MAP3K7"/> <bbox w="80.0" h="40.0" x="3900.0" y="1170.0"/> </glyph> <glyph class="macromolecule" id="s645_sa576"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TAB2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TAB2"/> <bbox w="80.0" h="40.0" x="3900.0" y="1220.0"/> </glyph> </glyph> <glyph class="complex" id="s174_csa13" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CHUK:IKBKG:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC Maps_Modules_end References_begin: complex PMID‭:15145317 The activated IKK complex, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription References_end </body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="3555.0" y="1306.5"/> <glyph class="macromolecule" id="s89_sa66"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="3563.0" y="1313.5"/> <glyph class="state variable" id="_524362cc-578f-4a2b-aca2-ee760812a9ae"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3638.0" y="1328.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s88_sa65"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="3564.0" y="1359.5"/> <glyph class="state variable" id="_4c6258ac-2ba1-487c-9b56-c7180ff9d01b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3559.0" y="1374.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s87_sa64"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="CHUK"/> <bbox w="80.0" h="40.0" x="3565.0" y="1404.5"/> </glyph> </glyph> <glyph class="complex" id="s615_csa46" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CSF2:CSF2RA:CSF2RB Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="s610"/> <bbox w="182.5" h="125.0" x="3678.75" y="527.5"/> <glyph class="macromolecule" id="s614_sa536"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24669294 SCF2 (GM-CSF) is assosiated with M1 phenotype of macrophages PMID:12928384 GM-CSF enhances monocyte APC function. GM-CSF increases surface class II MHC expression and decreases the relative level of the invariant chain-derived peptide, CLIP, bound to surface class II molecules. GM-CSF also increases expression of the costimulatory molecules CD86 and CD40. Additional analyses of the class II pathway revealed that GM-CSF increases total protein and RNA levels of HLA-DR, DM, and DOalpha. Expression of class II transactivator (CIITA) types I and III, but not IV, transcripts increases in response to GM-CSF. Furthermore, GM-CSF increases the amount of CIITA associated with the DR promoter. Thus, our data argue that the proinflammatory role of GM-CSF is mediated in part through increased expression of key molecules involved in the class II MHC pathway via induction of CIITA. PMID: 24030977 SCF2 (GM-CSF) promotes the immunosuppressive activity of glioma-infiltrating myeloid cells (MDSC) through upregulation of expression of interleukin-4 receptor-α. PMID:22698406 Granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. PMID:20406969 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="CSF2"/> <bbox w="80.0" h="40.0" x="3690.0" y="540.0"/> </glyph> <glyph class="macromolecule" id="s617_sa535"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits References_end </body> </html> </notes> <label text="CSF2RB"/> <bbox w="80.0" h="50.0" x="3773.75" y="582.5"/> <glyph class="unit of information" id="_a05a4d50-6bd7-4c58-80c9-28cbc58621a6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3791.25" y="577.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s616_sa534"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2RA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits References_end </body> </html> </notes> <label text="CSF2RA"/> <bbox w="80.0" h="50.0" x="3698.75" y="582.5"/> <glyph class="unit of information" id="_22db84b3-8b97-4f00-832e-d6aefcff2371"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3716.25" y="577.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1082_sa982"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="3780.0" y="540.0"/> <glyph class="state variable" id="_5d0b8f69-b5d1-458c-9c12-b9121d005576"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3775.0" y="555.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s610_csa45" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CSF2RA:CSF2RB Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits References_end </body> </html> </notes> <label text="s610"/> <bbox w="195.0" h="90.0" x="3642.5" y="405.0"/> <glyph class="macromolecule" id="s613_sa533"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2RB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits References_end </body> </html> </notes> <label text="CSF2RB"/> <bbox w="80.0" h="50.0" x="3740.0" y="415.0"/> <glyph class="unit of information" id="_04b51255-e332-4529-bd86-df17adfe62b7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3757.5" y="410.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s612_sa532"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF2RA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12393492 CSF2 acts via heterodimer receptor contains CSF2RA and SSF2RB subunits References_end </body> </html> </notes> <label text="CSF2RA"/> <bbox w="80.0" h="50.0" x="3660.0" y="415.0"/> <glyph class="unit of information" id="_e2b4ae48-8226-4a65-aa75-0988b6b71ca7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3677.5" y="410.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s591_csa43" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CSF1:CSF1R Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R References_end </body> </html> </notes> <label text="s591"/> <bbox w="100.0" h="120.0" x="2610.0" y="510.0"/> <glyph class="macromolecule" id="s593_sa516"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:24669294 SCF1 (M-CSF) is assosiated with M2 phenotype of macrophages References_end </body> </html> </notes> <label text="CSF1"/> <bbox w="80.0" h="40.0" x="2620.0" y="520.0"/> </glyph> <glyph class="macromolecule" id="s592_sa515"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CSF1R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:10705574 CSF1 acts via CSF1R PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of CSF1R protein level. References_end </body> </html> </notes> <label text="CSF1R"/> <bbox w="80.0" h="50.0" x="2620.0" y="565.0"/> <glyph class="unit of information" id="_6a47b71c-e030-493e-8adc-1176b629b292"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2637.5" y="560.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s582_csa42" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CXCL12:CXCR4 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="s582"/> <bbox w="100.0" h="120.0" x="2290.0" y="485.0"/> <glyph class="macromolecule" id="s590_sa514"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCR4 Identifiers_end Maps_Modules_begin: MODULE:RECRUITMENT_OF_IMMUNE_CELLS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:20644254 HIF2a induces macrophage migration via upregulation of CXCR4, FN1 expression and upregulation of M-CSFR protein level. PMID:22025564 PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="80.0" h="50.0" x="2300.0" y="540.0"/> <glyph class="unit of information" id="_b6dc44fc-acae-4e34-a5de-67e89196173a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2317.5" y="535.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s583_sa505"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CXCL12 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS Maps_Modules_end References_begin: PMID:20644254 CXCR4, the receptor for the chemokine CXCL12 (also known as SDF-1), also plays an important role in facilitating macrophage migration in vivo. PMID:22025564 PGE(2) was essential both for expression of functional CXCR4 in cancer-associated MDSCs and for production of its ligand CXCL12 by tumor cells. Frequencies of CD11b(+)CD14(+)CD33(+)CXCR4(+) MDSCs closely correlated with CXCL12 and PGE(2) levels in patient ascites. MDSCs migrated toward ovarian cancer ascites in a CXCR4-dependent manner that required COX2 activity and autocrine PGE(2) production. References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="2300.0" y="495.0"/> </glyph> </glyph> <glyph class="complex" id="s647_csa47" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CHUK:IKBKG:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC Maps_Modules_end References_begin: complex PMID‭:15145317 The activated IKK complex, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation.Ser536 is phoshorylated downstream of RAGE signaling in MDSC. References_end </body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="3785.0" y="1306.5"/> <glyph class="macromolecule" id="s649_sa580"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="3793.0" y="1313.5"/> <glyph class="state variable" id="_b1d5a314-75cb-453f-b4b1-f32c4baa5594"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="3863.0" y="1328.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s650_sa579"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="3794.0" y="1359.5"/> <glyph class="state variable" id="_879b1c81-6bb5-4498-b639-318dfd21406f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3786.5" y="1374.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s648_sa578"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="CHUK"/> <bbox w="80.0" h="40.0" x="3795.0" y="1404.5"/> </glyph> </glyph> <glyph class="complex" id="s214_csa18" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL6R:SOCS3:gp130* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R/SOCS3"/> <bbox w="184.0" h="135.0" x="3338.0" y="512.5"/> <glyph class="macromolecule" id="s127_sa104"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="3350.0" y="525.0"/> <glyph class="state variable" id="_8e426acb-bfba-4833-bc0f-d9f7458c9902"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="3412.5" y="522.541"/> </glyph> <glyph class="unit of information" id="_9cebbd79-e385-4863-9bf9-a2a9e6f19ad3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3367.5" y="520.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s126_sa103"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="3350.0" y="575.0"/> <glyph class="unit of information" id="_29732ead-6a8c-4067-bb2f-8528e36e677c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3367.5" y="570.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s132_sa102"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SOCS3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. PMID:12754507 IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling. References_end </body> </html> </notes> <label text="SOCS3"/> <bbox w="80.0" h="40.0" x="3430.0" y="540.0"/> </glyph> </glyph> <glyph class="complex" id="s178_csa4" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID: 19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. References_end </body> </html> </notes> <label text="RELA:p50"/> <bbox w="140.0" h="174.5" x="3411.5" y="1733.5"/> <glyph class="macromolecule" id="s20_sa17"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation. Ser536 is phoshorylated downstream of RAGE signaling in MDSC. References_end </body> </html> </notes> <label text="RELA"/> <bbox w="120.5" h="58.5" x="3429.75" y="1750.75"/> <glyph class="state variable" id="_41cf62bc-9bff-45e9-bd42-e0e3d5238275"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3422.25" y="1775.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s235_sa16"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NFKB1 MODULE:MACROPHAGE PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="118.5" h="66.5" x="3422.25" y="1814.75"/> <glyph class="unit of information" id="_b6ab55ad-3e5c-405f-8918-97af06ac460c"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3456.5" y="1809.75"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s291_csa14" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:NFKBIA:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC CASCADE:IL10 Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="3864.0" y="1510.5"/> <glyph class="macromolecule" id="s293_sa70"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3879.0" y="1617.5"/> <glyph class="unit of information" id="_323ec9da-fafa-4c77-b40b-474f748c6bc5"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3894.0" y="1612.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s292_sa69"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation. Ser536 is phoshorylated downstream of RAGE signaling in MDSC. References_end </body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="3879.0" y="1572.5"/> <glyph class="state variable" id="_4a2ef1f3-3ec1-4be3-82c0-ee951ce22e71"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3874.0" y="1587.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s93_sa68"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10542212 The primary level of control of NFkB heterodimer is through its interaction with the inhibitorprotein NFKBIA (IkBa). IL10 inhibits TNF-dependent degradation of NFKBIA. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via prevention of degradation of IkBa PMID:17485448, PMID:10542212 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. References_end </body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="3877.5" y="1526.5"/> <glyph class="state variable" id="_0c87fcdd-a181-4a54-a2e8-c6d9209bbc0f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3872.5" y="1541.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s176_csa16" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CHUK:IKBKG:IKK_beta_*:TNIP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: complex PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. PMID:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 References_end </body> </html> </notes> <label text="IKK/TNIP3 complex"/> <bbox w="189.0" h="158.0" x="3645.5" y="1031.0"/> <glyph class="macromolecule" id="s106_sa77"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CHUK Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="CHUK"/> <bbox w="80.0" h="40.0" x="3663.5" y="1128.0"/> </glyph> <glyph class="macromolecule" id="s104_sa78"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKB Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="3662.5" y="1083.0"/> <glyph class="state variable" id="_fd364292-483c-43f0-bd0a-231a26389bac"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3657.5" y="1098.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s105_sa79"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IKBKG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. References_end </body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="3661.5" y="1037.0"/> <glyph class="state variable" id="_5cbbb087-0f80-41d4-bd26-bace34451e35"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3736.5" y="1052.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s107_sa80"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNIP3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG. It results in inhibition of‭ ‬FNKBIA phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling‭ ‬downstream of IL10. PMID:17485448, PMID:10542212 Inhibition of NfkB signaling downstream of ABIN3 inhibits expression of IL8, IL6, TNFa, IL12p40 () References_end </body> </html> </notes> <label text="TNIP3"/> <bbox w="80.0" h="40.0" x="3747.5" y="1037.0"/> </glyph> </glyph> <glyph class="complex" id="s305_csa15" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:NFKBIA:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC CASCADE:IL10 Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="3537.5" y="1511.0"/> <glyph class="macromolecule" id="s307_sa75"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="3552.5" y="1618.0"/> <glyph class="unit of information" id="_c89bd849-787b-400a-b8f2-746e880362d7"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3567.5" y="1613.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s306_sa74"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RELA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:19171876 NFkB signaling via RELA:p50 heterodimer provides expression of proinflamatory cytokines and realisation of M1 phenotype of macrophages. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via inhibition of p65 nuclear migration in inflammatory marophages PMID:10521409, PMID:18802069 The endogenous IKK complex, overexpressed IKKs, and recombinant IKKbeta efficiently phosphorylated the Ser536 residue of p65 in vivo and in vitro, that is important foe NFKB signaling activation. Ser536 is phoshorylated downstream of RAGE signaling in MDSC. References_end </body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="3550.0" y="1570.0"/> <glyph class="state variable" id="_12b081b2-f536-4b7b-adcd-12a5f413d212"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3542.5" y="1585.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s101_sa73"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKBIA Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:10542212 The primary level of control of NFkB heterodimer is through its interaction with the inhibitorprotein NFKBIA (IkBa). IL10 inhibits TNF-dependent degradation of NFKBIA. PMID:17550372, PMID:9743347 IL13 inhibits NFκB activation via prevention of degradation of IkBa PMID:17485448, PMID:10542212 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. References_end </body> </html> </notes> <label text="NFKBIA"/> <bbox w="80.0" h="40.0" x="3551.0" y="1527.0"/> <glyph class="state variable" id="_a79f58e5-3303-46fd-a9eb-38978a121046"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3543.5" y="1542.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s993_sa900" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BIRC3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. References_end </body> </html> </notes> <label text="BIRC3"/> <bbox w="80.0" h="40.0" x="5440.0" y="2155.0"/> </glyph> <glyph class="macromolecule" id="s668_sa592" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. References_end </body> </html> </notes> <label text="IRAK2"/> <bbox w="80.0" h="40.0" x="4900.0" y="1135.0"/> </glyph> <glyph class="macromolecule" id="s991_sa898" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HDAC1 HGNC:4852 ENTREZ:3065 UNIPROT:Q13547 GENECARDS:HDAC1 HUGO:HDAC2 HGNC:4853 ENTREZ:3066 UNIPROT:Q92769 GENECARDS:HDAC2 HUGO:HDAC3 HGNC:4854 ENTREZ:8841 UNIPROT:O15379 GENECARDS:HDAC3 HUGO:HDAC4 HGNC:14063 ENTREZ:9759 UNIPROT:P56524 GENECARDS:HDAC4 HUGO:HDAC5 HGNC:14068 ENTREZ:10014 UNIPROT:Q9UQL6 GENECARDS:HDAC5 HUGO:HDAC6 HGNC:14064 ENTREZ:10013 UNIPROT:Q9UBN7 GENECARDS:HDAC6 HUGO:HDAC7 HGNC:14067 ENTREZ:51564 UNIPROT:Q8WUI4 GENECARDS:HDAC7 HUGO:HDAC8 HGNC:13315 ENTREZ:55869 UNIPROT:Q9BY41 GENECARDS:HDAC8 HUGO:HDAC10 HGNC:18128 ENTREZ:83933 UNIPROT:Q969S8 GENECARDS:HDAC10 HUGO:HDAC11 HGNC:19086 ENTREZ:79885 UNIPROT:Q96DB2 GENECARDS:HDAC11 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGES MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: REACTOME:56408 KEGG:3065 ATLASONC:GC_HDAC1 WIKI:HDAC1 REACTOME:56410 KEGG:3066 ATLASONC:HDAC2ID40803ch6q22 WIKI:HDAC2 REACTOME:401336 KEGG:8841 ATLASONC:HDAC3ID40804ch5q31 WIKI:HDAC3 REACTOME:56414 KEGG:9759 ATLASONC:GC_HDAC4 WIKI:HDAC4 REACTOME:415622 KEGG:10014 ATLASONC:GC_HDAC5 WIKI:HDAC5 REACTOME:56418 KEGG:10013 ATLASONC:GC_HDAC6 WIKI:HDAC6 REACTOME:412089 KEGG:9734 ATLASONC:GC_HDAC7 WIKI:HDAC7 REACTOME:148335 KEGG:55869 ATLASONC:GC_HDAC8 WIKI:HDAC8 0 0 REACTOME:412605 KEGG:83933 ATLASONC:GC_HDAC10 WIKI:HDAC10 1 1 REACTOME:56406 KEGG:79885 ATLASONC:GC_HDAC11 WIKI:HDAC11 PMID:17689680 HDACs provide STAT1 deacetylation and activation. References_end </body> </html> </notes> <label text="HDAC*"/> <bbox w="80.0" h="40.0" x="5000.0" y="1695.0"/> </glyph> <glyph class="macromolecule" id="s930_sa834" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induced IFNB expression through IRF1. TNF-induced Ifnb1 expression was completely abrogated in IRF1-deficient macrophages. References_end </body> </html> </notes> <label text="INFB1"/> <bbox w="80.0" h="40.0" x="4820.0" y="2313.5"/> </glyph> <glyph class="macromolecule" id="s929_sa833" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induces IFNA expression in macrophages References_end </body> </html> </notes> <label text="INFA1"/> <bbox w="80.0" h="40.0" x="4720.0" y="2313.5"/> </glyph> <glyph class="nucleic acid feature" id="s928_sa832" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induced IFNB expression through IRF1. TNF-induced Ifnb1 expression was completely abrogated in IRF1-deficient macrophages. 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TNF-induced Ifnb1 expression was completely abrogated in IRF1-deficient macrophages. PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. References_end </body> </html> </notes> <label text="IFNB1"/> <bbox w="70.0" h="25.0" x="4825.0" y="2221.0"/> </glyph> <glyph class="nucleic acid feature" id="s925_sa829" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNA1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:18345002 TNF induces IFNA expression in macrophages References_end </body> </html> </notes> <label text="IFNA1"/> <bbox w="70.0" h="25.0" x="4725.0" y="2221.0"/> </glyph> <glyph class="nucleic acid feature" id="s910_sa809" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:16007092 GSK3 induces IFNG secretion downstream of TLR signaling. References_end </body> </html> </notes> <label text="INFG"/> <bbox w="90.0" h="25.0" x="4915.0" y="2271.0"/> <glyph class="unit of information" id="_928dadfb-7b35-433c-9a2e-798f687c1314"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4950.0" y="2266.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s909_sa808" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages References_end </body> </html> </notes> <label text="INFG"/> <bbox w="70.0" h="25.0" x="4925.0" y="2221.0"/> </glyph> <glyph class="macromolecule" id="s908_sa807" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID: 16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="80.0" h="40.0" x="4910.0" y="2313.5"/> </glyph> <glyph class="macromolecule" id="s856_sa755" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. References_end </body> </html> </notes> <label text="IRAK3"/> <bbox w="80.0" h="40.0" x="4600.0" y="1185.0"/> </glyph> <glyph class="source and sink" id="s841_sa741" compartmentRef="c8_ca8"> <label text="sa696_degraded"/> <bbox w="30.0" h="30.0" x="5490.0" y="2043.5"/> </glyph> <glyph class="macromolecule" id="s803_sa715" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BIRC2 HUGO:BIRC3 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. References_end </body> </html> </notes> <label text="cIAP*"/> <bbox w="80.0" h="40.0" x="5580.0" y="2105.0"/> </glyph> <glyph class="macromolecule" id="s802_sa713" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:BIRC2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. References_end </body> </html> </notes> <label text="BIRC2"/> <bbox w="80.0" h="40.0" x="5435.0" y="2088.5"/> </glyph> <glyph class="nucleic acid feature" id="s789_sa703" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:RIPK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12193701 INFG upregulates RIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="70.0" h="25.0" x="5335.0" y="1972.5"/> </glyph> <glyph class="nucleic acid feature" id="s788_sa702" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:RIPK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="90.0" h="25.0" x="5455.0" y="1972.5"/> <glyph class="unit of information" id="_5228624f-7911-448d-9984-42cf0c7f9fa6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5490.0" y="1967.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s787_sa701" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12193701 INFG upregulates TNFR1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1 References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="90.0" h="25.0" x="5570.0" y="1866.0"/> <glyph class="unit of information" id="_212587f5-a4ef-4396-86e9-f6f17884dcef"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5605.0" y="1861.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s782_sa697" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:RIPK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="5575.0" y="1968.5"/> <glyph class="state variable" id="_711fd4cf-4877-41cf-bde7-7e4d169ba282"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5650.0" y="1983.9336"/> </glyph> </glyph> <glyph class="macromolecule" id="s781_sa696" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="5580.0" y="2025.0"/> <glyph class="state variable" id="_752cfc06-b5d0-431f-ae82-dd4de9ef3e0a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5655.0" y="2038.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s801_sa695" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TRADD Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14730360 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="5575.0" y="1918.5"/> </glyph> <glyph class="nucleic acid feature" id="s733_sa659" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SOCS1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12433365, PMID:10485906 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 References_end </body> </html> </notes> <label text="SOCS1"/> <bbox w="90.0" h="25.0" x="4880.0" y="1946.0"/> <glyph class="unit of information" id="_a800093e-a224-466c-aa12-c2f8e34543b0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4915.0" y="1941.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s732_sa658" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="90.0" h="25.0" x="4535.0" y="1927.5"/> <glyph class="unit of information" id="_22f3cca0-0457-46e1-8c9e-2bc83bf30d2a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4570.0" y="1922.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s777_sa657" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SOCS1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12433365, PMID:10485906 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 References_end </body> </html> </notes> <label text="SOCS1"/> <bbox w="70.0" h="25.0" x="4890.0" y="2006.0"/> </glyph> <glyph class="nucleic acid feature" id="s730_sa656" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12433365 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="70.0" h="25.0" x="4545.0" y="1867.5"/> </glyph> <glyph class="macromolecule" id="s729_sa655" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SOCS1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: SOCS-1 decreases IFNG signaling via inhiviting the catalytic activity of JAKs. PMID:12811837 SOCS-1 overexpression resulted in a nearly complete loss of IFNG responsiveness in macrophages. PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:12193701 INFG upregulates TNFR1 and RIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. References_end </body> </html> </notes> <label text="SOCS1"/> <bbox w="100.0" h="70.0" x="4876.0" y="1838.5"/> </glyph> <glyph class="macromolecule" id="s728_sa654" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="80.0" h="40.0" x="4540.0" y="1980.0"/> <glyph class="state variable" id="_fbcd8cbc-133f-46d0-a9a7-28a1e0032098"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4535.0" y="1995.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s727_sa651" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="90.0" h="25.0" x="4645.0" y="967.5"/> <glyph class="unit of information" id="_1d9eb797-1a35-4f98-939d-44ac4fe2fed5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4680.0" y="962.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s723_sa646" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PTPN11 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19833085, PMID:15699106, PMID:12270932 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. References_end </body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="4865.0" y="1578.5"/> </glyph> <glyph class="macromolecule" id="s722_sa645" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:PTPN2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19833085, PMID:15699106, PMID:12138178 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. PMID:19833085 Probably, acetylation of STAT1 on lysine residues 410 and 413 in the nucleus results in enhanced interaction with TCP45 (PTPN2) and increased dephosphorylation References_end </body> </html> </notes> <label text="PTPN2"/> <bbox w="80.0" h="40.0" x="4765.0" y="1578.5"/> </glyph> <glyph class="macromolecule" id="s720_sa643" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CREBBP Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19879327 STAT1 is acetylated by CBP at the lysine residues K410 and K413. PMID:16007092 GSK3B induces RELA (p65) interaction with CBP and activates downstream NF-kB signaling end expression of proinflammatory cytokines. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. PMID:12417340 IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator in macrophages. References_end </body> </html> </notes> <label text="CBP*"/> <bbox w="80.0" h="40.0" x="4625.0" y="1698.5"/> </glyph> <glyph class="macromolecule" id="s719_sa642" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID: PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. References_end </body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="4895.0" y="1648.5"/> <glyph class="state variable" id="_0680eb30-ff4e-43a4-8fdc-ff2b6df06b73"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="4964.806" y="1683.5"/> </glyph> <glyph class="state variable" id="_480da30d-f840-47cd-846a-c3f941b513d0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4890.0" y="1662.2123"/> </glyph> </glyph> <glyph class="macromolecule" id="s718_sa641" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:STAT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID: PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. References_end </body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="4725.0" y="1648.5"/> <glyph class="state variable" id="_98cff3e5-9448-4a23-8464-3ecd667ccf62"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="4794.806" y="1683.5"/> </glyph> <glyph class="state variable" id="_c412a257-c970-4092-babf-9beac119797c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4717.5" y="1662.2123"/> </glyph> </glyph> <glyph class="macromolecule" id="s703_sa631" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:CD14 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="CD14"/> <bbox w="80.0" h="40.0" x="4730.0" y="875.0"/> </glyph> <glyph class="macromolecule" id="s691_sa616" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:LY96 Identifiers_end Maps_Modules_begin: MODEULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="80.0" h="40.0" x="4730.0" y="775.0"/> </glyph> <glyph class="macromolecule" id="s690_sa615" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TIRAP Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. References_end </body> </html> </notes> <label text="TIRAP"/> <bbox w="80.0" h="40.0" x="4730.0" y="725.0"/> </glyph> <glyph class="macromolecule" id="s689_sa614" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="4730.0" y="825.0"/> </glyph> <glyph class="macromolecule" id="s686_sa611" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TLR2 HUGO:TLR4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. References_end </body> </html> </notes> <label text="TLR2/4*"/> <bbox w="80.0" h="50.0" x="4730.0" y="660.0"/> <glyph class="unit of information" id="_53fe31f8-a21a-439d-887c-cdfdd42ad9af"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4747.5" y="655.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s634_sa565"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HMGB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19197071, PMID:21372296 HMGB1 is secreted by M1 activated macrophages and macrophages expressed TLR4. PMID:17704786 HMGB1 is secreted by dying tumor cells. PMID:25164013 HMGB1 activates MDSCs via the NF-κB pathway It increases MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. References_end </body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="5290.0" y="535.0"/> </glyph> <glyph class="macromolecule" id="s667_sa590" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 References_end </body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="5020.0" y="1135.0"/> </glyph> <glyph class="macromolecule" id="s641_sa589" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6. References_end </body> </html> </notes> <label text="IRAK1"/> <bbox w="80.0" h="40.0" x="4760.0" y="1395.0"/> <glyph class="state variable" id="_9e4c7d8f-8051-45ae-95ba-953819bb0a28"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4755.0" y="1410.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s644_sa583" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TRAF6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="4675.0" y="1288.5"/> </glyph> <glyph class="macromolecule" id="s644_sa575" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TRAF6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="4513.75" y="1286.0"/> </glyph> <glyph class="macromolecule" id="s669_sa572" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IRAK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6. References_end </body> </html> </notes> <label text="IRAK1"/> <bbox w="80.0" h="40.0" x="4600.0" y="1395.0"/> <glyph class="state variable" id="_01f37fda-119b-4ed8-a2e2-cc5d03140a86"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4592.5" y="1410.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s850_sa570" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HMGB1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:19197071, PMID:21372296 HMGB1 is secreted by M1 activated macrophages and macrophages expressed TLR4. PMID:17704786 HMGB1 is secreted by dying tumor cells. PMID:25164013 HMGB1 activates MDSCs via the NF-κB pathway It increases MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. References_end </body> </html> </notes> <label text="HMGB1"/> <bbox w="80.0" h="40.0" x="4750.0" y="1025.0"/> </glyph> <glyph class="macromolecule" id="s529_sa450" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNGR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. 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References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="5500.0" y="1340.0"/> <glyph class="state variable" id="_6ee81309-7604-4594-92fc-e2f6b5cb5a6a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5495.0" y="1359.9602"/> </glyph> <glyph class="unit of information" id="_dbe14014-4649-42ca-ae09-9f7acbb7439d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5517.5" y="1335.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s526_sa448" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MIR125B1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:16243976 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 ion resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR References_end </body> </html> </notes> <label text="MIR125B1"/> <bbox w="90.0" h="25.0" x="5475.0" y="1492.5"/> <glyph class="unit of information" id="_cdcce805-b5ff-46d2-85e7-b6437d8047a0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5505.0" y="1487.5"/> </glyph> </glyph> <glyph class="complex" id="s804_csa58" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:RBCK1:RNF31:SHARPIN Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modiﬁed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. PMID:24958845 NFkB activation (IkBa degradation) downstream of TNF is LUBAC-dependent. References_end </body> </html> </notes> <label text="LUBAC"/> <bbox w="110.0" h="150.0" x="5550.0" y="2193.5"/> <glyph class="macromolecule" id="s807_sa718"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RNF31 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1. References_end </body> </html> </notes> <label text="RNF31"/> <bbox w="80.0" h="40.0" x="5570.0" y="2203.5"/> </glyph> <glyph class="macromolecule" id="s806_sa717"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:SHARPIN Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 References_end </body> </html> </notes> <label text="SHARPIN"/> <bbox w="80.0" h="40.0" x="5570.0" y="2243.5"/> </glyph> <glyph class="macromolecule" id="s805_sa716"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RBCK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 References_end </body> </html> </notes> <label text="RBCK1"/> <bbox w="80.0" h="40.0" x="5570.0" y="2283.5"/> </glyph> </glyph> <glyph class="complex" id="s654_csa49" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD14:HMGB1:LY96:MYD88:TIRAP:TLR2/4* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC Maps_Modules_end References_begin: PMID:17704786, PMID:20547845 HMGB1 interacts with TLR4/LY96(MD2) complex and is internalized with the TLR4 complex after cell surface binding. PMID:16267105 HMGB1 interacts with TLR2. TLR2/TLR4 signaling downstream of HMGB1 acts via MYD88 pathway. PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. Transfection of dominant negative MyD88 or TIRAP inhibited almost all of the HMGB1- and LPS-induced NF-κB activation. MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="s654"/> <bbox w="198.75" h="180.0" x="4981.25" y="835.0"/> <glyph class="macromolecule" id="s706_sa632"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD14 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="CD14"/> <bbox w="80.0" h="40.0" x="4990.0" y="895.0"/> </glyph> <glyph class="macromolecule" id="s674_sa571"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TIRAP Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. References_end </body> </html> </notes> <label text="TIRAP"/> <bbox w="80.0" h="40.0" x="5070.0" y="945.0"/> </glyph> <glyph class="macromolecule" id="s673_sa569"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="4990.0" y="945.0"/> </glyph> <glyph class="macromolecule" id="s672_sa567"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LY96 Identifiers_end Maps_Modules_begin: MODEULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="80.0" h="40.0" x="4990.0" y="845.0"/> </glyph> <glyph class="macromolecule" id="s671_sa566"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TLR2 HUGO:TLR4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. References_end </body> </html> </notes> <label text="TLR2/4*"/> <bbox w="80.0" h="50.0" x="5070.0" y="890.0"/> <glyph class="unit of information" id="_54a42b6f-7b8f-47af-b6be-4468fa7691ab"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5087.5" y="885.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s660_csa50" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD14:HMGB1:IRAK2:IRAK4:LY96:MYD88:TIRAP:TLR2/4* Identifiers_end Maps_Modules_begin: MODEULE:MACROPHAGE MODEULE:MDSC Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. Transfection of dominant negative MyD88 or TIRAP inhibited almost all of the HMGB1- and LPS-induced NF-κB activation. MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 References_end </body> </html> </notes> <label text="s654"/> <bbox w="227.5" h="220.625" x="5346.25" y="1024.6875"/> <glyph class="macromolecule" id="s707_sa629"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:CD14 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:23508573 Signaling of HMGB1 through TLR4 in macrophages requires CD14 References_end </body> </html> </notes> <label text="CD14"/> <bbox w="80.0" h="40.0" x="5370.0" y="1085.0"/> </glyph> <glyph class="macromolecule" id="s682_sa574"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRAK4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 References_end </body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="5370.0" y="1175.0"/> </glyph> <glyph class="macromolecule" id="s681_sa584"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TLR2 HUGO:TLR4 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID: PMID:16713974, PMID:14607900 IL10 and Stat3 mediate feedback inhibition of TLR signaling. TLR2/TLR4 induces IL10 expression. IL10 inhibits exppression of TNF downstream of TLR. References_end </body> </html> </notes> <label text="TLR2/4*"/> <bbox w="80.0" h="50.0" x="5460.0" y="1080.0"/> <glyph class="unit of information" id="_4bdd1a55-66b4-411f-8a38-cd7ae6ef7b65"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5477.5" y="1075.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s680_sa585"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:LY96 Identifiers_end Maps_Modules_begin: MODEULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <label text="LY96"/> <bbox w="80.0" h="40.0" x="5370.0" y="1035.0"/> </glyph> <glyph class="macromolecule" id="s679_sa586"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:MYD88 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="5370.0" y="1135.0"/> </glyph> <glyph class="macromolecule" id="s678_sa587"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TIRAP Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODEULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. References_end </body> </html> </notes> <label text="TIRAP"/> <bbox w="80.0" h="40.0" x="5460.0" y="1135.0"/> </glyph> <glyph class="macromolecule" id="s676_sa573"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 MyD88 recruits members of the death domain-containing serine/threonine IL-1R-associated kinase (IRAK) family. References_end </body> </html> </notes> <label text="IRAK2"/> <bbox w="80.0" h="40.0" x="5460.0" y="1175.0"/> </glyph> </glyph> <glyph class="complex" id="s527_csa40" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IFNGR1:IFNGR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. PMID: 19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2. Ligand engagement of the IFNG receptor leads to activation of receptor-associated Jak1 and Jak2 and phosphorylation of a receptor tyrosine residue (Y440) that serves as a docking site for STAT1, which exists in a latent state in the cytoplasm. References_end </body> </html> </notes> <label text="IFNGR"/> <bbox w="120.0" h="130.0" x="5670.0" y="1270.0"/> <glyph class="macromolecule" id="s710_sa452"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNGR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR2"/> <bbox w="80.0" h="50.0" x="5690.0" y="1325.0"/> <glyph class="unit of information" id="_c0efe75f-97d7-4592-889e-3d723a7006bf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5707.5" y="1320.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s709_sa451"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNGR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="5690.0" y="1285.0"/> <glyph class="state variable" id="_52138380-5835-423f-8f95-f09d4b3da905"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5685.0" y="1304.9602"/> </glyph> <glyph class="unit of information" id="_8e31a9de-3c07-4320-8452-235083bead86"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5707.5" y="1280.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s712_csa53" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IFNG:IFNGR1:IFNGR2:JAK1:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. PMID: 19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2. Ligand engagement of the IFNG receptor leads to activation of receptor-associated Jak1 and Jak2 and phosphorylation of a receptor tyrosine residue (Y440) that serves as a docking site for STAT1, which exists in a latent state in the cytoplasm. References_end </body> </html> </notes> <label text="IFNGR"/> <bbox w="205.0" h="170.0" x="5737.5" y="1440.0"/> <glyph class="macromolecule multimer" id="s717_sa640"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID: 16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="86.0" h="46.0" x="5797.0" y="1452.0"/> <glyph class="unit of information" id="_1ed6baca-d996-4261-839d-de06af098ced"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="5830.0" y="1447.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s716_sa639"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="5847.5" y="1540.0"/> <glyph class="state variable" id="_64d6da45-9a32-4f80-a78b-f40272b359f5"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5842.5" y="1555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s715_sa638"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="5757.5" y="1540.0"/> <glyph class="state variable" id="_bd780e80-0d19-42ec-b19f-6e0e3b72b6ed"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5752.5" y="1555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s714_sa634"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNGR2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR2"/> <bbox w="80.0" h="50.0" x="5760.0" y="1490.0"/> <glyph class="unit of information" id="_c05e8e20-2c1e-4d82-85a6-7dd2f6f12349"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5777.5" y="1485.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s713_sa633"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IFNGR1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="5850.0" y="1490.0"/> <glyph class="state variable" id="_2cfc47ac-7820-4cfe-a538-60c8b53c8f67"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5842.5" y="1509.9602"/> </glyph> <glyph class="unit of information" id="_f7cd98a3-083f-4104-b6b0-c95eb278080f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5867.5" y="1485.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s778_sa693" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="5890.0" y="1860.0"/> <glyph class="unit of information" id="_83c054a8-d63c-4986-ab21-d9e0281fe52b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5907.5" y="1855.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s711_sa635"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID: 16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="86.0" h="46.0" x="6077.0" y="1192.0"/> <glyph class="unit of information" id="_e549507d-22ed-48fa-a4c2-fe4b4babe24b"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6110.0" y="1187.0"/> </glyph> </glyph> <glyph class="complex" id="s824_csa60" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:STAT1:TNFR1* Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14607933 TNF induces the association of STAT-1 and TNFR1 in a tyrosine phosphorylation-independent manner, and and this association attenuates TNF-alpha-mediated NF-kappaB activation but formation of the TNFR1:STAT-1α complex is inhibited upon inclusion of IFNG . IFNG limits STAT-1 availability to the TNFR1 by depleting STAT from the cytoplasm, thus allowing for optimal NF-kappaB activation upon TNF ligation. References_end </body> </html> </notes> <label text="TNFR1*:STAT1"/> <bbox w="100.0" h="130.0" x="5870.0" y="1650.0"/> <glyph class="macromolecule" id="s826_sa728"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="5880.0" y="1705.0"/> <glyph class="unit of information" id="_a1538839-bff7-428d-b5b5-d647c5fe663b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5897.5" y="1700.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s825_sa727"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:STAT1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. PMID: PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:14607900 FNG inhibits IL10 signalind via STAT1. STAT1 overexpression prevents STAT3 homodimerization. PMID:12193701, PMID:11830590 CD40 expression is upregulated by STAT1 downstream of INFG and NF-kB downstream of TNF. PMID:12193701 INFG upregulates TNFR1 and PIPK1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. References_end </body> </html> </notes> <label text="STAT1"/> <bbox w="70.0" h="45.0" x="5885.0" y="1657.5"/> <glyph class="state variable" id="_55252e7f-1918-4a50-aa44-3c9b7da68abc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5949.83" y="1697.5"/> </glyph> <glyph class="state variable" id="_a99024f9-b667-4b60-8763-2ffbe86df9fb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5877.5" y="1673.5514"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s815_csa59" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:FADD:RIPK1:TNF:TNFR1*:TRADD:TRAF2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modiﬁed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. References_end </body> </html> </notes> <label text="TNFR1"/> <bbox w="210.0" h="180.0" x="5925.0" y="2170.0"/> <glyph class="macromolecule" id="s832_sa724"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RIPK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="5940.0" y="2280.0"/> <glyph class="state variable" id="_044ffd07-cfff-47ad-8648-e7fbd9d5dbc8"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="6010.0" y="2295.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s831_sa723"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRADD Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14730360 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="5940.0" y="2230.0"/> </glyph> <glyph class="macromolecule" id="s833_sa722"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="5940.0" y="2180.0"/> <glyph class="state variable" id="_a19d7f91-ff08-4a51-a1db-17efc05b2cdf"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="6010.0" y="2193.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s830_sa721"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, PMID:14625680 TNF and IFNG cooperate in the activation of macrophages. References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="6035.0" y="2180.0"/> </glyph> <glyph class="macromolecule" id="s829_sa720"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="6035.0" y="2225.0"/> <glyph class="unit of information" id="_4a093444-e66f-4f44-9432-7c33f5d586eb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6052.5" y="2220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s828_sa719"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FADD Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="FADD"/> <bbox w="80.0" h="40.0" x="6040.0" y="2280.0"/> </glyph> </glyph> <glyph class="complex" id="s790_csa56" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:FADD:RIPK1:TNF:TNFR1*:TRADD:TRAF2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. References_end </body> </html> </notes> <label text="TNFR1"/> <bbox w="210.0" h="180.0" x="5985.0" y="1905.0"/> <glyph class="macromolecule" id="s814_sa712"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:RIPK1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="6010.0" y="2015.0"/> <glyph class="state variable" id="_b1a63cdf-d0bb-492c-a205-b5f4c71ade52"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6085.0" y="2030.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s813_sa711"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRADD Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14730360 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="6010.0" y="1965.0"/> </glyph> <glyph class="macromolecule" id="s812_sa710"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="6000.0" y="1920.0"/> <glyph class="state variable" id="_85001855-2060-49cb-a558-4caf5cb8d304"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6075.0" y="1933.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s811_sa709"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, PMID:14625680 TNF and IFNG cooperate in the activation of macrophages. References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="6095.0" y="1915.0"/> </glyph> <glyph class="macromolecule" id="s810_sa708"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:TNFRSF1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="6095.0" y="1960.0"/> <glyph class="unit of information" id="_ce6e3535-999c-41e9-a117-612a90c77f4d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6112.5" y="1955.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s809_sa698"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FADD Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="FADD"/> <bbox w="80.0" h="40.0" x="6110.0" y="2020.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s535_sa456"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IFNG Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12413632 IFNG is a major factor of M1 activation of macrophages. PMID:6425450 Monoclonal antibody to IFNG inhibits macrophage tumoricidal activities. PMID:11964313 INFG potentiates TLR signaling and NFkB activation downstream of TLR. PMID:9864217 IFNG cooperates with TNF and TLR signaling in NF-kB activation. PMID:19833085 IFNG achieves strong activation effects is by enhancing macrophage responsiveness to other inflammatory stimuli, such as TLR ligands and TNF. PMID:14607900, PMID:16713974 IFNG impairs IL-10 anti-inflammatory activity. PMID:10485906 IFNG downregulates IL4 signaling pathway via SOCS1. PMID:16713974 INFG signaling inhibits p38 activation PMID:15814715, PMID:18272812, PMID:17016554 STAT1 is involeved in immunosupresive activity of M2 macrophages and MDSC, probably downstream of IFNG. activation of MSCs is initiated in response to IFN-gamma, presumably produced in situ by antitumor T cells in the tumor microenvironment. PMID: 16424049 The secretion of interleukin (IL)-10 and transforming growth factor-beta by Gr-1(+)CD115(+) MSCs and iNOS expression was induced and enhanced, respectively, on IFN-gamma stimulation. References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="80.0" h="40.0" x="6280.0" y="1195.0"/> </glyph> <glyph class="macromolecule" id="s760_sa257"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TNF Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:21133840 TNF is a pleiotropic cytokine produced by many different types of cells in the body. However, cells of the monocytic lineage—such as macrophages, astroglia, microglia, Langerhans cells, Kupffer cells, and alveolar macrophages—are the primary synthesizers of TNF PMID:1431106 TNF induced tumoricidal activity of macrophages. PMID:14607933, PMID:14625680 TNF and IFNG cooperate in the activation of macrophages. References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="6360.0" y="1915.0"/> </glyph> <glyph class="nucleic acid feature" id="s767_sa686" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:FOS Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713974 INFG signaling ingibits FOS expression References_end </body> </html> </notes> <label text="FOS"/> <bbox w="70.0" h="25.0" x="3440.0" y="2346.0"/> </glyph> <glyph class="simple chemical" id="s999_sa907"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. PMID:20490273, PMID:17016559 L-arginine plays a critical role in the immunosuppressive activity of MDSC. T-cell proliferation and activation depends on the availability of L-arginine. L-arginine is a nonessential amino acid and is a substrate for two enzymes, inducible NO synthase (iNOS or NOS2) and arginase 1. MDSCs express both enzymes at high levels [36]. Recent data suggests that the increased activity of arginase 1 and iNOS in MDSC leads to enhanced L-arginine catabolism, which results in a reduction or depletion of L-arginine in the microenvironment. The lack of L-arginine results in inhibition of T-cell function References_end </body> </html> </notes> <label text="L-arginine"/> <bbox w="100.0" h="28.0" x="2590.0" y="4246.0"/> </glyph> <glyph class="simple chemical" id="s1000_sa908"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC Maps_Modules_end References_begin: PMID:21680779, PMID:22816309 Myeloid-derived suppressor cell inhibit the IFN response in immune cells (splenocytes) via inhibition of STAT1 phosphorylation by NO (downstream of iNOS). But probably it doesn't work for macrophages where inhibition of INOS reduces STAT1 phosphorylation. References_end </body> </html> </notes> <label text="NO"/> <bbox w="70.0" h="25.0" x="4245.0" y="4197.5"/> </glyph> <glyph class="phenotype" id="s585_sa509"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <label text="Migration into tumor"/> <bbox w="220.0" h="35.0" x="2110.0" y="62.5"/> </glyph> <glyph class="macromolecule" id="s1004_sa912" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:AGER MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS PMID:18802069, PMID:23248262 S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function.. </body> </html> </notes> <label text="RAGE*"/> <bbox w="80.0" h="50.0" x="1840.0" y="545.0"/> <glyph class="unit of information" id="_1c5d8cef-b0b3-46f7-a7ef-8784faf4239f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1857.5" y="540.0"/> </glyph> </glyph> <glyph class="complex" id="s1007_csa77" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:18802069, PMID:23248262 MDSC synthesize and secrete S100A8/A9 heterodimers PMID: 25614008 The S100A8–S100A9 heterodimer has been documented to have physiologically relevant functions in vivo </body> </html> </notes> <label text="s1007"/> <bbox w="100.0" h="120.0" x="1990.0" y="830.0"/> <glyph class="macromolecule" id="s1011_sa914"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:S100A8 MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="2000.0" y="890.0"/> </glyph> <glyph class="macromolecule" id="s1012_sa915"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="2000.0" y="840.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1008_sa916" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:S100A8 MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="2110.0" y="1020.0"/> </glyph> <glyph class="macromolecule" id="s1009_sa917" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="2010.0" y="1020.0"/> </glyph> <glyph class="complex" id="s1010_csa78"> <label text="s1007"/> <bbox w="100.0" h="120.0" x="1920.0" y="220.0"/> <glyph class="macromolecule" id="s1005_sa918"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:S100A8 MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="1930.0" y="280.0"/> </glyph> <glyph class="macromolecule" id="s1006_sa919"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="1930.0" y="230.0"/> </glyph> </glyph> <glyph class="complex" id="s1013_csa79" compartmentRef="c10_ca10"> <label text="s1013"/> <bbox w="120.0" h="180.0" x="1880.0" y="630.0"/> <glyph class="macromolecule" id="s1014_sa913"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:AGER MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS PMID:18802069, PMID:23248262 S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function.. </body> </html> </notes> <label text="RAGE*"/> <bbox w="80.0" h="50.0" x="1900.0" y="735.0"/> <glyph class="unit of information" id="_9ace3ec0-203c-4466-bb38-873b88a39bb2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1917.5" y="730.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1015_sa920"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. PMID:18809714, PMID:12645005 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. S100A9 may suppress myeloid cell differentiation via persistent up-regulation of ROS in progenitor cells. </body> </html> </notes> <label text="S100A9"/> <bbox w="80.0" h="40.0" x="1900.0" y="650.0"/> </glyph> <glyph class="macromolecule" id="s1016_sa921"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:S100A8 MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS HUGO:S100A9 PMID:18802069, PMID:23248262 S100A8/A9 proteins are chemotactic for MDSC. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor (probably RAGE) for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration and immunosuppressive function. </body> </html> </notes> <label text="S100A8"/> <bbox w="80.0" h="40.0" x="1900.0" y="690.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1018_sa925" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CEBPB MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. </body> </html> </notes> <label text="CEBPB"/> <bbox w="80.0" h="40.0" x="1570.0" y="1720.0"/> </glyph> <glyph class="nucleic acid feature" id="s1019_sa926" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CEBPB MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. </body> </html> </notes> <label text="CEBPB"/> <bbox w="90.0" h="25.0" x="1455.0" y="1727.5"/> <glyph class="unit of information" id="_205f7c2b-b4f9-4a21-9937-3663391001f4"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1490.0" y="1722.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1020_sa927" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CEBPB MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS PMID:20581311 STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF-responsive myeloid progenitor expansion. STAT3 directly controls G-CSF-dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. </body> </html> </notes> <label text="CEBPB"/> <bbox w="70.0" h="25.0" x="1355.0" y="1727.5"/> </glyph> <glyph class="nucleic acid feature" id="s1022_sa929" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STAT3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. </body> </html> </notes> <label text="STAT3"/> <bbox w="70.0" h="25.0" x="965.0" y="1907.5"/> </glyph> <glyph class="nucleic acid feature" id="s1023_sa930" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STAT3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. </body> </html> </notes> <label text="STAT3"/> <bbox w="90.0" h="25.0" x="955.0" y="1857.5"/> <glyph class="unit of information" id="_2b1618f9-ae10-4c3a-a9d8-7f919ef5866b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="990.0" y="1852.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1024_sa931" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR17 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. </body> </html> </notes> <label text="MIR17"/> <bbox w="90.0" h="25.0" x="1135.0" y="1717.5"/> <glyph class="unit of information" id="_60ea492d-c10f-490f-b552-99a9707ebe3f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1165.0" y="1712.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1025_sa932" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR20A MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. </body> </html> </notes> <label text="MIR20A"/> <bbox w="90.0" h="25.0" x="975.0" y="1717.5"/> <glyph class="unit of information" id="_35d2fa76-3bc5-4250-b3b7-1327cdc5014c"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1005.0" y="1712.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1026_sa933" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS HUGO:CD33 PMID:21383238 CD33 and CD11b are typical markers of MDSC cells </body> </html> </notes> <label text="CD33"/> <bbox w="80.0" h="50.0" x="1880.0" y="3555.0"/> <glyph class="unit of information" id="_c9b90a52-ff56-4dba-a47f-0ca4080f95ef"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1897.5" y="3550.0"/> </glyph> </glyph> <glyph class="complex" id="s1028_csa80" compartmentRef="c8_ca8"> <label text="s1028"/> <bbox w="100.0" h="120.0" x="1120.0" y="1540.0"/> <glyph class="nucleic acid feature" id="s1030_sa936"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR17 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. </body> </html> </notes> <label text="MIR17"/> <bbox w="90.0" h="25.0" x="1125.0" y="1567.5"/> <glyph class="unit of information" id="_bd1b66b8-0c49-4de3-89d9-89039c22f350"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1155.0" y="1562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1029_sa937"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STAT3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. </body> </html> </notes> <label text="STAT3"/> <bbox w="90.0" h="25.0" x="1125.0" y="1597.5"/> <glyph class="unit of information" id="_4b403c54-f38a-4171-ba8a-d6d15ba08755"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1160.0" y="1592.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1031_csa81" compartmentRef="c8_ca8"> <label text="s1031"/> <bbox w="100.0" h="120.0" x="990.0" y="1540.0"/> <glyph class="nucleic acid feature" id="s1033_sa934"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STAT3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. miR-17-5p and miR-20a also reduced the transcriptional and protein levels of p47phox and gp91phox, two subunits of NADPH oxidase. </body> </html> </notes> <label text="STAT3"/> <bbox w="90.0" h="25.0" x="995.0" y="1587.5"/> <glyph class="unit of information" id="_af1697da-43fb-498b-be43-1568a2a0eb50"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1030.0" y="1582.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1032_sa935"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR20A MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:21383238 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells and macrophages by modulating STAT3 expression. </body> </html> </notes> <label text="MIR20A"/> <bbox w="90.0" h="25.0" x="995.0" y="1557.5"/> <glyph class="unit of information" id="_f8b6502b-fa6c-45d9-8b67-c99949434953"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1025.0" y="1552.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s1034_sa938" compartmentRef="c8_ca8"> <label text="csa81_degraded"/> <bbox w="30.0" h="30.0" x="1095.0" y="1695.0"/> </glyph> <glyph class="nucleic acid feature" id="s1035_sa939" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF1 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="NCF1"/> <bbox w="70.0" h="25.0" x="3245.0" y="2917.5"/> </glyph> <glyph class="nucleic acid feature" id="s1036_sa940" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBB MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="CYBB"/> <bbox w="70.0" h="25.0" x="3025.0" y="2907.5"/> </glyph> <glyph class="complex" id="s1045_csa82" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>MODULE:MDSC PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. PMID:18809714 S100A9 regulates myeloid cell differentiation via reactive oxygen species (ROS), probabli via NAPDH oxidase. </body> </html> </notes> <label text="NADPH oxidase"/> <bbox w="250.0" h="230.0" x="3045.0" y="3235.0"/> <glyph class="macromolecule" id="s1038_sa941"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBB MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="CYBB"/> <bbox w="80.0" h="40.0" x="3090.0" y="3250.0"/> </glyph> <glyph class="macromolecule" id="s1039_sa942"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBA MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="CYBA"/> <bbox w="80.0" h="40.0" x="3090.0" y="3300.0"/> </glyph> <glyph class="macromolecule" id="s1040_sa943"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF1 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="NCF1"/> <bbox w="80.0" h="40.0" x="3180.0" y="3270.0"/> </glyph> <glyph class="macromolecule" id="s1041_sa944"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF4 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="NCF4"/> <bbox w="80.0" h="40.0" x="3180.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s1042_sa945"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF2 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="NCF2"/> <bbox w="80.0" h="40.0" x="3180.0" y="3360.0"/> </glyph> <glyph class="macromolecule" id="s1043_sa946"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:RAC1 HUGO:RAC2 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="3090.0" y="3350.0"/> </glyph> <glyph class="simple chemical" id="s1044_sa948"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="3065.0" y="3397.5"/> </glyph> <glyph class="simple chemical" id="s1046_sa949"> <label text="heme"/> <bbox w="70.0" h="25.0" x="3135.0" y="3407.5"/> </glyph> <glyph class="simple chemical" id="s1047_sa950"> <label text="FAD"/> <bbox w="70.0" h="25.0" x="3205.0" y="3407.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1048_sa951" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF2 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="NCF2"/> <bbox w="80.0" h="40.0" x="3220.0" y="3180.0"/> </glyph> <glyph class="macromolecule" id="s1049_sa952" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF4 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="NCF4"/> <bbox w="80.0" h="40.0" x="3220.0" y="3130.0"/> </glyph> <glyph class="macromolecule" id="s1050_sa953" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF1 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="NCF1"/> <bbox w="80.0" h="40.0" x="3220.0" y="3080.0"/> </glyph> <glyph class="macromolecule" id="s1052_sa955" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBA MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="CYBA"/> <bbox w="80.0" h="40.0" x="3060.0" y="3130.0"/> </glyph> <glyph class="macromolecule" id="s1053_sa956" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBB MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="CYBB"/> <bbox w="80.0" h="40.0" x="3060.0" y="3080.0"/> </glyph> <glyph class="complex" id="s1054_csa83" compartmentRef="c8_ca8"> <label text="s1054"/> <bbox w="100.0" h="120.0" x="2930.0" y="3120.0"/> <glyph class="macromolecule" id="s1051_sa954"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:RAC1 HUGO:RAC2 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19372727 The enzyme responsible for O2•- production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two transmembrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="2940.0" y="3140.0"/> </glyph> <glyph class="simple chemical" id="s1055_sa957"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="2945.0" y="3187.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s1056_sa958" compartmentRef="c8_ca8"> <label text="heme"/> <bbox w="70.0" h="25.0" x="3145.0" y="3127.5"/> </glyph> <glyph class="simple chemical" id="s1057_sa959" compartmentRef="c8_ca8"> <label text="FAD"/> <bbox w="70.0" h="25.0" x="3145.0" y="3077.5"/> </glyph> <glyph class="nucleic acid feature" id="s1058_sa960" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NCF1 MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="NCF1"/> <bbox w="90.0" h="25.0" x="3235.0" y="2977.5"/> <glyph class="unit of information" id="_c07d6643-7f4c-4177-a2f9-2c5f0259ac96"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3270.0" y="2972.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1059_sa962" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBB MODULE:MDSC MODULE:NO_ROS_PRODUCTION PMID:19380816, PMID:21383238 The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). STAT3 upregulates expression of NOX2 subunits, primarily p47(NCF1) and gp91(CYBB) in MDSC, In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. </body> </html> </notes> <label text="CYBB"/> <bbox w="90.0" h="25.0" x="3015.0" y="2977.5"/> <glyph class="unit of information" id="_33125aea-bd3f-4792-a816-ca00066b1299"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3050.0" y="2972.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1061_sa963" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC HUGO:CEBPA MODULE:CORE_SIGNALING_PATHWAYS PMID:20581311, PMID:11340171 CEBPA downregulates MYC gene expression and provides granulocytic differentiation of myeloid cells.. </body> </html> </notes> <label text="CEBPA"/> <bbox w="80.0" h="40.0" x="1570.0" y="1660.0"/> </glyph> <glyph class="macromolecule" id="s1066_sa968" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:20237318 GSF3R is a receptor for GSF3 in myeloid cells. The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. </body> </html> </notes> <label text="CSF3R"/> <bbox w="80.0" h="50.0" x="2720.0" y="395.0"/> <glyph class="unit of information" id="_b3efd519-2816-495e-9a86-93436075bfa7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2737.5" y="390.0"/> </glyph> </glyph> <glyph class="complex" id="s1067_csa84" compartmentRef="c10_ca10"> <label text="s1067"/> <bbox w="100.0" h="120.0" x="2810.0" y="470.0"/> <glyph class="macromolecule" id="s1068_sa969"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:20237318 GSF3R is a receptor for GSF3 in myeloid cells. The receptor for CSF3 (CSF3R) belongs to the cytokine receptor type I superfamily, which engages the canonical Janus kinase (Jak)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinase, and PKB/Akt pathways. </body> </html> </notes> <label text="CSF3R"/> <bbox w="80.0" h="50.0" x="2820.0" y="525.0"/> <glyph class="unit of information" id="_0dc40a21-6901-47dc-affb-a14ab1a7e2cf"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2837.5" y="520.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1069_sa970"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CSF3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID: 22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="2820.0" y="480.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1071_sa972"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC HUGO:HSPA1A HGNC:5232 ENTREZ:3303 UNIPROT:P08107 GENECARDS:HSPA1A REACTOME:56682 KEGG:3303 ATLASONC:GC_HSPA1A WIKI:HSPA1A HUGO:HSPA1B HGNC:5233 ENTREZ:3304 UNIPROT:P08107 GENECARDS:HSPA1B REACTOME:56682 KEGG:3304 ATLASONC:GC_HSPA1B WIKI:HSPA1B heat shock 70kDa protein 1B HUGO:HSPA1B HGNC:5233 ENTREZ:3304 UNIPROT:P08107 GENECARDS:HSPA1B REACTOME:56682 KEGG:3304 ATLASONC:GC_HSPA1B WIKI:HSPA1B HUGO:HSPA1A HGNC:5232 ENTREZ:3303 UNIPROT:P08107 GENECARDS:HSPA1A REACTOME:56682 KEGG:3303 ATLASONC:GC_HSPA1A WIKI:HSPA1A heat shock 70kDa protein 1-like HUGO:HSPA1L HGNC:5234 ENTREZ:3305 UNIPROT:P34931 GENECARDS:HSPA1L KEGG:3305 ATLASONC:GC_HSPA1L WIKI:HSPA1L "heat shock 70kD protein 1A", HSPA1 MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:20093776 Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells via TLR2/MyD88 dependent IL6 expression. </body> </html> </notes> <label text="HSP70*"/> <bbox w="80.0" h="40.0" x="4980.0" y="460.0"/> </glyph> <glyph class="macromolecule" id="s1072_sa849"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:9716487 Interleukin-6-type cytokine signalling acts through the gp130/Jak/STAT pathway. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC References_end </body> </html> </notes> <label text="IL6"/> <bbox w="80.0" h="40.0" x="3170.0" y="160.0"/> </glyph> <glyph class="complex" id="s1074_csa85" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL6R:gp130* Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:12754507 IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="195.0" h="138.40625" x="2962.5" y="510.79688"/> <glyph class="macromolecule" id="s1075_sa973"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6ST Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="2974.125" y="565.7969"/> <glyph class="state variable" id="_3eb5cf15-3023-47e8-a7b6-c8b82628a0e0"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="3036.625" y="563.3379"/> </glyph> <glyph class="unit of information" id="_c19e35e7-57f7-47ef-8a0e-ff3773bc183c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2991.625" y="560.7969"/> </glyph> </glyph> <glyph class="macromolecule" id="s1076_sa974"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IL6R Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="2974.125" y="525.7969"/> <glyph class="unit of information" id="_8fa438eb-a3b3-4335-a9a4-649e196a7627"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2991.625" y="520.7969"/> </glyph> </glyph> <glyph class="macromolecule" id="s1073_sa975"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:IL6 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:20093776 IL6 signaling ilduces STAT3 phosphorylation in MDSC cells. PMID:9716487 Interleukin-6-type cytokine signalling acts through the gp130/Jak/STAT pathway. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC References_end </body> </html> </notes> <label text="IL6"/> <bbox w="80.0" h="40.0" x="3057.5" y="599.2031"/> </glyph> </glyph> <glyph class="macromolecule" id="s1077_sa976" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IRF8 MODEULE:MACROPHAGE MODEULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS PMID:24091328 (a) Irf8-deficient mice generated myeloid populations highly homologous to tumor-induced MDSCs with respect to phenotype, function, and gene expression profiles; (b) IRF-8 overexpression in mice attenuated MDSC accumulation and enhanced immunotherapeutic efficacy; (c) the MDSC-inducing factors G-CSF and GM-CSF facilitated IRF-8 downregulation via STAT3- and STAT5-dependent pathways; and (d) IRF-8 levels in MDSCs of breast cancer patients declined with increasing MDSC frequency, implicating IRF-8 as a negative regulator in human MDSC biology. IRF-8 levels are depressed in MDSCs of breast cancer patients. PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice (black columns) following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, as well as from IRF-1 null mice. </body> </html> </notes> <label text="IRF8"/> <bbox w="80.0" h="40.0" x="4290.0" y="1975.0"/> </glyph> <glyph class="macromolecule" id="s1078_sa978" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:IRF1 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 PMID:12417340 IRF-8/ICSBP and IRF-1 cooperatively stimulate mouse IL-12 p40 promoter activity in macrophages. IRF-1 can be acetylated by p300. p300 is recruited to the IL-12p40 promoter depending on both ICSBP and IRF-1 and acts as coactivator. PMID:16597464 IRF-8 and IRF-1 are the target genes in activated macrophages. The expression levels of CXCL16, H28, IL-17R, LIF, MAP4K4, MMP9, MYC, PCDH7, PML, and SOCS7 were signiﬁcantly increased in macrophages extracted form WT mice following activation for 4 h with IFNG and LPS. However, no changes in the expression of these genes were observed in cells extracted from IRF-8, References_end </body> </html> </notes> <label text="IRF1"/> <bbox w="80.0" h="40.0" x="4540.0" y="2065.0"/> <glyph class="state variable" id="_af98a945-14db-4d89-b1f5-db176295fbb6"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="4530.0" y="2080.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1079_sa979" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STAT5A HUGO:STAT5B MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. </body> </html> </notes> <label text="STAT5*"/> <bbox w="80.0" h="40.0" x="3610.0" y="730.0"/> <glyph class="state variable" id="_91e33326-6428-467e-b229-0320a1b21e33"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3605.0" y="745.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1080_sa980" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STAT5A HUGO:STAT5B MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. </body> </html> </notes> <label text="STAT5*"/> <bbox w="80.0" h="40.0" x="3610.0" y="810.0"/> <glyph class="state variable" id="_06781e7f-d600-4b92-9b78-ce6f9c207dc2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3602.5" y="825.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1081_sa981" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:JAK2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="3560.0" y="580.0"/> <glyph class="state variable" id="_c6014ea4-07c0-4e59-9adf-af0d0bee3201"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3555.0" y="595.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1083_sa983" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IRF8 MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. </body> </html> </notes> <label text="IRF8"/> <bbox w="70.0" h="25.0" x="4285.0" y="1872.5"/> </glyph> <glyph class="nucleic acid feature" id="s1084_sa984" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IRF8 MODULE:MACROPHAGE MODULE:MDSC MODULE:CORE_SIGNALING_PATHWAYS PMID:24091328 G-CSF downregulates IRF8 expression via STAT3 and GM-CSF via STAT5. IRF8 inhibition provides immunosuppressive functions of MDSC. </body> </html> </notes> <label text="IRF8"/> <bbox w="90.0" h="25.0" x="4275.0" y="1922.5"/> <glyph class="unit of information" id="_e1221200-9951-4b46-9eec-d660f72d557c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4310.0" y="1917.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s1085_sa986" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. </body> </html> </notes> <label text="Arachidonic acid"/> <bbox w="105.0" h="32.5" x="4257.5" y="2623.75"/> </glyph> <glyph class="simple chemical" id="s1086_sa987" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="4125.0" y="2627.5"/> </glyph> <glyph class="simple chemical" id="s1088_sa989"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="2095.0" y="257.5"/> </glyph> <glyph class="macromolecule" id="s1089_sa990" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. PMID:16186186 PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. </body> </html> </notes> <label text="PTGER4"/> <bbox w="80.0" h="50.0" x="2140.0" y="515.0"/> <glyph class="unit of information" id="_44cf5a5a-b57f-4ba3-88c4-9dc1072b5c1f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2157.5" y="510.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1090_sa991" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. </body> </html> </notes> <label text="PTGER2"/> <bbox w="80.0" h="50.0" x="2030.0" y="525.0"/> <glyph class="unit of information" id="_a068b215-a80f-4718-bb52-d60f4e3fc7af"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2047.5" y="520.0"/> </glyph> </glyph> <glyph class="complex" id="s1092_csa86" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>MODULE:MDSC PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. </body> </html> </notes> <label text="s1092"/> <bbox w="100.0" h="120.0" x="2040.0" y="620.0"/> <glyph class="macromolecule" id="s1094_sa992"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. </body> </html> </notes> <label text="PTGER2"/> <bbox w="80.0" h="50.0" x="2050.0" y="665.0"/> <glyph class="unit of information" id="_310ca170-4c3f-48a4-8039-e99655bc3af7"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2067.5" y="660.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s1093_sa994"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="2055.0" y="637.5"/> </glyph> </glyph> <glyph class="complex" id="s1095_csa87" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>MODULE:MDSC PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. </body> </html> </notes> <label text="s1095"/> <bbox w="100.0" h="120.0" x="2150.0" y="610.0"/> <glyph class="macromolecule" id="s1096_sa993"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC MODULE:RECRUITMENT_OF_IMMUNE_CELLS PMID:22025564 PGE2 induces expression of CXCR4 in MDSC Inhibition of COX2 or the PGE2 receptors EP2/EP4 in MDSCs suppressed expression of CXCR4 and MDSC responsiveness to CXCL12 or ovarian cancer ascites. PMID:16186186 PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. </body> </html> </notes> <label text="PTGER4"/> <bbox w="80.0" h="50.0" x="2160.0" y="655.0"/> <glyph class="unit of information" id="_4d8982fc-95c9-4767-b1c0-9bc802bd739f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2177.5" y="650.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s1091_sa995"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> PMID:22025564 COX2 catalyses synthesis of PGE2 in MDSC. </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="2165.0" y="627.5"/> </glyph> </glyph> <glyph class="complex" id="s1099_csa88" compartmentRef="c10_ca10"> <label text="s1099"/> <bbox w="110.0" h="140.0" x="4070.0" y="480.0"/> <glyph class="macromolecule" id="s1102_sa997"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL1R MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. </body> </html> </notes> <label text="IL1R1"/> <bbox w="80.0" h="50.0" x="4080.0" y="545.0"/> <glyph class="unit of information" id="_9962f8b5-44ff-41cf-8313-9586b215e26a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4097.5" y="540.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1103_sa998"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC HUGO:IL1RAP MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. </body> </html> </notes> <label text="IL1RAP"/> <bbox w="80.0" h="50.0" x="4080.0" y="495.0"/> <glyph class="unit of information" id="_178a2ad7-3dab-4a18-9d4f-221ad3b4675f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4097.5" y="490.0"/> </glyph> </glyph> </glyph> <glyph class="simple chemical" id="s1111_sa1002"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:20414655, PMID:2880923, PMID:3115975 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. </body> </html> </notes> <label text="Cysteine"/> <bbox w="70.0" h="25.0" x="3855.0" y="4297.5"/> </glyph> <glyph class="simple chemical" id="s1112_sa1004"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:20414655, PMID:2880923, PMID:3115975 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. </body> </html> </notes> <label text="Cystine"/> <bbox w="70.0" h="25.0" x="2925.0" y="4287.5"/> </glyph> <glyph class="macromolecule" id="s1113_sa346" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID: PMID:2422040 MHC II provides antigen presentation by human monocytes. PMID:16243976 INFG upregulates surface expression of MHC II. IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 resulted in increased surface expression of MHC II. PMID:15644117 HMGB1 upregulates the expression of MHC class II molecules on the surface of macrophages. References_end </body> </html> </notes> <label text="MHC class II*"/> <bbox w="80.0" h="40.0" x="5290.0" y="3135.0"/> <glyph class="unit of information" id="_f46925b0-3f82-4f6e-a03b-6975fd0c5f98"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5307.5" y="3130.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1115_sa8" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:JAK1 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:‭21115385 ‭JAK1 is a member of the Janus kinase family. ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) PMID: PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="800.0" y="1390.0"/> <glyph class="state variable" id="_a42d8aca-ef2a-4609-9913-7b823d4987b4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="795.0" y="1405.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s1116_sa1005" compartmentRef="c8_ca8"> <label text="Cystine"/> <bbox w="70.0" h="25.0" x="2925.0" y="3817.5"/> </glyph> <glyph class="simple chemical" id="s1117_sa1006" compartmentRef="c8_ca8"> <label text="Cysteine"/> <bbox w="70.0" h="25.0" x="3855.0" y="3797.5"/> </glyph> <glyph class="complex" id="s1118_csa91" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:20414655, PMID:2880923, PMID:3115975 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. </body> </html> </notes> <label text="s1118"/> <bbox w="105.0" h="145.0" x="2797.5" y="4007.5"/> <glyph class="macromolecule" id="s1119_sa1007"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION HUGO:SLC7A11 PMID:20414655, PMID:2880923, PMID:3115975, PMID:20028852 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. PMID:20028852 MDSCs express the cystine transporter but lack cystathionase and the ASC neutral amino acid transporter Therefore, macrophages, DCs, and MDSCs can import cystine; however, unlike macrophages and DCs, MDSCs are unable to export cysteine. MDSC sequester cystine and prevent T cells from obtaining cysteine which is important for Tcell activation. </body> </html> </notes> <label text="SLC7A11"/> <bbox w="80.0" h="40.0" x="2812.5" y="4027.5"/> </glyph> <glyph class="macromolecule" id="s1121_sa1012"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SLC3A2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98). References_end </body> </html> </notes> <label text="SLC3A2"/> <bbox w="80.0" h="50.0" x="2812.5" y="4072.5"/> <glyph class="unit of information" id="_91cd9a18-0b0d-4d58-9a8a-1ed40664e585"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2830.0" y="4067.5"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1120_sa1011" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE MODULE:MDSC MODULE:NO_ROS_PRODUCTION HUGO:SLC7A11 PMID:20414655, PMID:2880923, PMID:3115975, PMID:20028852 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. PMID:20028852 MDSCs express the cystine transporter but lack cystathionase and the ASC neutral amino acid transporter Therefore, macrophages, DCs, and MDSCs can import cystine; however, unlike macrophages and DCs, MDSCs are unable to export cysteine. MDSC sequester cystine and prevent T cells from obtaining cysteine which is important for Tcell activation. </body> </html> </notes> <label text="SLC7A11"/> <bbox w="80.0" h="40.0" x="2750.0" y="3940.0"/> </glyph> <glyph class="macromolecule" id="s1122_sa1015" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:NO_ROS_PRODUCTION HUGO:SLC7A10 PMID:20414655, PMID:2880923, PMID:3115975, PMID:20028852 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. 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MDSC sequester cystine and prevent T cells from obtaining cysteine which is important for Tcell activation. </body> </html> </notes> <label text="SLC7A10"/> <bbox w="80.0" h="40.0" x="3790.0" y="3910.0"/> </glyph> <glyph class="complex" id="s1123_csa92" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:20414655, PMID:2880923, PMID:3115975 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. </body> </html> </notes> <label text="s1123"/> <bbox w="100.0" h="130.0" x="3740.0" y="3975.0"/> <glyph class="macromolecule" id="s1125_sa1013"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:SLC3A2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:18250477 An IL-4-mediated LGALS3 (galectin-3) autocrine loop promotes alternative macrophage activation and is blocked by pharmacological inhibition of galectin-3 and its receptor SLC3A2 (CD98). References_end </body> </html> </notes> <label text="SLC3A2"/> <bbox w="80.0" h="50.0" x="3750.0" y="4030.0"/> <glyph class="unit of information" id="_69a9b3ab-f4fa-4a55-82d1-9e538f973062"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3767.5" y="4025.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1124_sa1014"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:NO_ROS_PRODUCTION HUGO:SLC7A10 PMID:20414655, PMID:2880923, PMID:3115975, PMID:20028852 Macrophages import cystine through their x c − transporter, reduce it to cysteine and then export the cysteine through their ASC neutral amino acid transporter. PMID:20028852 MDSCs express the cystine transporter but lack cystathionase and the ASC neutral amino acid transporter Therefore, macrophages, DCs, and MDSCs can import cystine; however, unlike macrophages and DCs, MDSCs are unable to export cysteine. MDSC sequester cystine and prevent T cells from obtaining cysteine which is important for Tcell activation. </body> </html> </notes> <label text="SLC7A10"/> <bbox w="80.0" h="40.0" x="3750.0" y="3985.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1126_sa1016" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE HUGO:TXN MODULE:NO_ROS_PRODUCTION PMID:20414655, PMID:18792398 Trx is one of the main intracellular oxido-reductases TXN expression is upregulated in activated macrophages, DC and probably macrophages secrete thioredoxin which reduces extracellular cystine to cysteine, which is then available for the uptake by T cells through their ASC transporter </body> </html> </notes> <label text="TXN"/> <bbox w="80.0" h="40.0" x="3390.0" y="3870.0"/> </glyph> <glyph class="macromolecule" id="s1127_sa1017"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE HUGO:TXN MODULE:NO_ROS_PRODUCTION PMID:20414655, PMID:18792398 Trx is one of the main intracellular oxido-reductases TXN expression is upregulated in activated macrophages, DC and probably macrophages secrete thioredoxin which reduces extracellular cystine to cysteine, which is then available for the uptake by T cells through their ASC transporter </body> </html> </notes> <label text="TXN"/> <bbox w="80.0" h="40.0" x="3390.0" y="4250.0"/> </glyph> <glyph class="macromolecule" id="s1128_sa1019" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF2 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. </body> </html> </notes> <label text="FGF2"/> <bbox w="80.0" h="40.0" x="1795.0" y="3441.5"/> </glyph> <glyph class="macromolecule" id="s1129_sa492"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:MMP9 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS Maps_Modules_end References_begin: PMID:11875494 MMPs plays important in the degradation and remodeling of the extracellular matrix at sites of inflammation. HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="80.0" h="40.0" x="2091.5" y="4142.5"/> </glyph> <glyph class="macromolecule" id="s1130_sa1018"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF2 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. </body> </html> </notes> <label text="FGF2"/> <bbox w="80.0" h="40.0" x="1890.0" y="4120.0"/> </glyph> <glyph class="nucleic acid feature" id="s1131_sa1020" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF2 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. </body> </html> </notes> <label text="FGF2"/> <bbox w="70.0" h="25.0" x="1800.0" y="3319.0"/> </glyph> <glyph class="nucleic acid feature" id="s1132_sa1021" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF2 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:18776941 Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. </body> </html> </notes> <label text="FGF2"/> <bbox w="90.0" h="25.0" x="1790.0" y="3389.0"/> <glyph class="unit of information" id="_3acea717-d9f4-4ec4-b24c-c75b9b55e99e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1825.0" y="3384.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1133_sa1022" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CSF3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID: 22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="4990.0" y="2650.0"/> </glyph> <glyph class="macromolecule" id="s1359_sa1032" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD2 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. TGF-β1-mediated arginase-1 induction was almost completely impaired in Smad2/3 DKO BMDMs. Smad2 and Smad3 inhibited iNOS promoter activities and additional TGF-β1 enhanced the suppressive effect of Smads STAT1 phosphorylation was enhanced and prolonged in Smad2/3 DKO BMDMs compared with WT BMDMs Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="1470.0" y="1080.0"/> <glyph class="state variable" id="_f21acc76-50ed-4407-aa7b-028648e81e14"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1465.0" y="1094.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s1358_sa1034" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD2 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. TGF-β1-mediated arginase-1 induction was almost completely impaired in Smad2/3 DKO BMDMs. Smad2 and Smad3 inhibited iNOS promoter activities and additional TGF-β1 enhanced the suppressive effect of Smads STAT1 phosphorylation was enhanced and prolonged in Smad2/3 DKO BMDMs compared with WT BMDMs Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="1470.0" y="1160.0"/> <glyph class="state variable" id="_6fd6d577-530a-45d6-b115-0f8bfa2da5e9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1462.5" y="1174.9681"/> </glyph> </glyph> <glyph class="macromolecule" id="s1326_sa1035" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD3 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. TGF-β1-mediated arginase-1 induction was almost completely impaired in Smad2/3 DKO BMDMs. Smad2 and Smad3 inhibited iNOS promoter activities and additional TGF-β1 enhanced the suppressive effect of Smads STAT1 phosphorylation was enhanced and prolonged in Smad2/3 DKO BMDMs compared with WT BMDMs Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="1690.0" y="1100.0"/> <glyph class="state variable" id="_911f244e-d34f-49e5-a744-4802cb359b9c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1682.5" y="1115.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1312_sa1036" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD3 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. TGF-β1-mediated arginase-1 induction was almost completely impaired in Smad2/3 DKO BMDMs. Smad2 and Smad3 inhibited iNOS promoter activities and additional TGF-β1 enhanced the suppressive effect of Smads STAT1 phosphorylation was enhanced and prolonged in Smad2/3 DKO BMDMs compared with WT BMDMs Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="1690.0" y="1030.0"/> <glyph class="state variable" id="_dac7dff0-2576-4c5f-9c5b-6b314c566b84"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1685.0" y="1045.0"/> </glyph> </glyph> <glyph class="complex" id="s1332_csa95" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocatio </body> </html> </notes> <label text="s1332"/> <bbox w="100.0" h="120.0" x="1670.0" y="1180.0"/> <glyph class="macromolecule" id="s1334_sa1037"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD3 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. TGF-β1-mediated arginase-1 induction was almost completely impaired in Smad2/3 DKO BMDMs. Smad2 and Smad3 inhibited iNOS promoter activities and additional TGF-β1 enhanced the suppressive effect of Smads STAT1 phosphorylation was enhanced and prolonged in Smad2/3 DKO BMDMs compared with WT BMDMs Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. 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This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="1680.0" y="1240.0"/> </glyph> </glyph> <glyph class="complex" id="s1360_csa96" compartmentRef="c8_ca8"> <label text="s1360"/> <bbox w="100.0" h="120.0" x="1520.0" y="1250.0"/> <glyph class="macromolecule" id="s1361_sa1039"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD4 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="1530.0" y="1300.0"/> </glyph> <glyph class="macromolecule" id="s1362_sa1040"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD2 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. PMID:22331441 SMAD2 and SMAD3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. TGF-β1-mediated arginase-1 induction was almost completely impaired in Smad2/3 DKO BMDMs. Smad2 and Smad3 inhibited iNOS promoter activities and additional TGF-β1 enhanced the suppressive effect of Smads STAT1 phosphorylation was enhanced and prolonged in Smad2/3 DKO BMDMs compared with WT BMDMs Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="1530.0" y="1260.0"/> <glyph class="state variable" id="_28ef1708-2091-48c9-8cdd-a96eab916ba8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1522.5" y="1274.9681"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1331_sa1033" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD4 MODULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:11792802, PMID: 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="1590.0" y="1140.0"/> </glyph> <glyph class="macromolecule" id="s1134_sa1041" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IRF3 MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="IRF3"/> <bbox w="80.0" h="40.0" x="4360.0" y="2075.0"/> <glyph class="state variable" id="_f7108d11-04ff-4dfc-a609-c6d1e54c51bc"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4355.0" y="2090.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1135_sa1042" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IRF3 MODULE:MACROPHAGE MODULE:CORE_SIGNALING_PATHWAYS PMID:22331441 Smad2/3 inhibited IFN-β production by suppressing IRF3 transcriptional activity. Smad2/3 somehow suppresses IRF3 phosphorylation. </body> </html> </notes> <label text="IRF3"/> <bbox w="80.0" h="40.0" x="4360.0" y="2155.0"/> <glyph class="state variable" id="_507a8b7e-4438-4d03-b900-d3246b91d8a2"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4352.5" y="2170.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1137_sa1044"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) PMID: 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. PMID: 24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. </body> </html> </notes> <label text="trILB1"/> <bbox w="80.0" h="40.0" x="4300.0" y="230.0"/> <glyph class="unit of information" id="_767074b3-b404-46f3-8c74-84a5505793c7"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4315.0" y="225.0"/> </glyph> </glyph> <glyph class="complex" id="s1139_csa90" compartmentRef="c10_ca10"> <label text="s1099"/> <bbox w="185.0" h="140.0" x="4205.0" y="540.0"/> <glyph class="macromolecule" id="s1140_sa999"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL1R MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. </body> </html> </notes> <label text="IL1R1"/> <bbox w="80.0" h="50.0" x="4215.0" y="605.0"/> <glyph class="unit of information" id="_5cb2fc71-84eb-4096-96a9-76800c672bc1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4232.5" y="600.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1141_sa1000"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MDSC HUGO:IL1RAP MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. </body> </html> </notes> <label text="IL1RAP"/> <bbox w="80.0" h="50.0" x="4215.0" y="555.0"/> <glyph class="unit of information" id="_0b947bfa-8cd3-4a56-9264-188781abf6fa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4232.5" y="550.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1138_sa1046"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) PMID: 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. PMID: 24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. </body> </html> </notes> <label text="trILB1"/> <bbox w="80.0" h="40.0" x="4300.0" y="560.0"/> <glyph class="unit of information" id="_ed0462b5-b5f5-4a50-a758-b26d98d8a9e5"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4315.0" y="555.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s1142_sa1047" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) PMID: 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. PMID: 24727385 Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC that promotes tumor growth. PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. mRNA expression of several NF-κB target genes such is IL6, IL1B,TNF are IL1B/NFkB dependent in MSDC PMID:17942936 IL-1R–deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1β–induced expansion of MDSC. IL-1Ra (IL-1R antagonis) −/− MDSC are more suppressive than BALB/c MDSC. </body> </html> </notes> <label text="trILB1"/> <bbox w="80.0" h="40.0" x="4120.0" y="900.0"/> <glyph class="unit of information" id="_c6ec3476-d185-42d5-bf84-94c2656681a6"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4135.0" y="895.0"/> </glyph> </glyph> <glyph class="complex" id="s1367_csa98" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>MODULE:MACROPHAGE MODULE:MDSC PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) PMID: 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. </body> </html> </notes> <label text="Inflammasome"/> <bbox w="110.0" h="150.0" x="4395.0" y="1025.0"/> <glyph class="macromolecule" id="s1363_sa1052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NLRP3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) </body> </html> </notes> <label text="NLRP3"/> <bbox w="80.0" h="40.0" x="4405.0" y="1115.0"/> </glyph> <glyph class="macromolecule" id="s1365_sa1053"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PYCARD MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) </body> </html> </notes> <label text="PYCARD"/> <bbox w="80.0" h="40.0" x="4405.0" y="1075.0"/> </glyph> <glyph class="macromolecule" id="s1364_sa1054"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CASP1 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3).After 2 hours of incubation, monocytes display clear activation of caspase-1 regardless of LPS stimulation. </body> </html> </notes> <label text="Caspase1*"/> <bbox w="80.0" h="40.0" x="4405.0" y="1035.0"/> </glyph> </glyph> <glyph class="complex" id="s1368_csa97" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>MODULE:MACROPHAGE MODULE:MDSC PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) PMID:20385749 The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. PMID: 23202296 (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. </body> </html> </notes> <label text="Inflammasome"/> <bbox w="110.0" h="150.0" x="4245.0" y="1005.0"/> <glyph class="macromolecule" id="s1369_sa1048"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NLRP3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) </body> </html> </notes> <label text="NLRP3"/> <bbox w="80.0" h="40.0" x="4255.0" y="1095.0"/> </glyph> <glyph class="macromolecule" id="s1370_sa1050"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PYCARD MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3) </body> </html> </notes> <label text="PYCARD"/> <bbox w="80.0" h="40.0" x="4255.0" y="1055.0"/> </glyph> <glyph class="macromolecule" id="s1366_sa1051"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CASP1 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID:19104081 Inflammasome is needfull for processing and release of IL-1beta in monocytes downstream of TLR2 or TLR4 signaling. It contains CASP1, Pycard, NLRP3 (NALP3). After 2 hours of incubation, monocytes display clear activation of caspase-1 regardless of LPS stimulation. </body> </html> </notes> <label text="cleaved Caspase1*"/> <bbox w="80.0" h="40.0" x="4260.0" y="1010.0"/> <glyph class="unit of information" id="_f63bbb9a-9810-4d26-a8d6-cf2f1486fa56"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="4275.0" y="1005.0"/> </glyph> </glyph> </glyph> <glyph class="simple chemical" id="s1371_sa1061"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>PMID:25043024 Lactic acid is sufficient to induce Vegf and Arg1 via HIF1α. Lactic acid, probably via HIF1A polarizes macrophages to an M2-Iike state that is critical for tumour growth </body> </html> </notes> <label text="lactic acid "/> <bbox w="70.0" h="25.0" x="2815.0" y="77.5"/> </glyph> <glyph class="macromolecule" id="s1375_sa1065" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:TYK2 Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: MODUULE:MACROPHAGE MODULE:IMMUNOSUPPRESSIVE_CYTOKINE_PATHWAYS PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="900.0" y="1280.0"/> <glyph class="state variable" id="_467cba74-604a-49a5-ac74-194a805da339"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="895.0" y="1295.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1376_sa438" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE MODULE:ANTIGEN_PRESENTATION_AND_IMMUNOSTIMULATORY_CHEKPOINTS Maps_Modules_end References_begin: PMID: PMID:2422040 MHC II provides antigen presentation by human monocytes. PMID:16243976 INFG upregulates surface expression of MHC II. IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 resulted in increased surface expression of MHC II. PMID:15644117 HMGB1 upregulates the expression of MHC class II molecules on the surface of macrophages. References_end </body> </html> </notes> <label text="MHC class II*"/> <bbox w="81.333336" h="46.0" x="5539.3335" y="3187.0"/> <glyph class="unit of information" id="_4a79f4ec-1019-44ae-99e6-43eeb949f084"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5557.5" y="3182.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1377_sa928"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CSF3 MODULE:MACROPHAGE MODULE:MDSC MODULE:IMMUNOSTIMULATORY_CYTOKINE_EXPRESSION MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS PMID: 22754783 CSF3 (G-CSF) secreted by tumors imduces MDSC signalings. PMID:20581311 G-CSF signaling by STAT3 controls c-myc transcription by regulating the ratio of C/EBPα to C/EBPβ at the c-myc promoter </body> </html> </notes> <label text="GSF3"/> <bbox w="80.0" h="40.0" x="2800.0" y="170.0"/> </glyph> <glyph class="phenotype" id="s159_sa131" compartmentRef="c10_ca10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:20856220, PMID:20144856, PMID:22277903 Macrophages and related cell types isolated from established metastatic tumors generally have an M2-like phenotype. They are oriented to tissue repair and remodelling, immunoregulation, and tumor promotion. References_end </body> </html> </notes> <label text="M2 phenotype of macrophages_or_MDSC"/> <bbox w="368.0" h="194.5" x="1556.0" y="3732.75"/> </glyph> <glyph class="macromolecule" id="s1379_sa1067" compartmentRef="c8_ca8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:FADD Identifiers_end Maps_Modules_begin: MODULE:IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. References_end </body> </html> </notes> <label text="FADD"/> <bbox w="80.0" h="40.0" x="5690.0" y="1910.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4d6d9ac5-eb9b-4ed0-95f0-c58138f8b6c6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12907458 Bcl-3‭ ‬interacted with NF-κB p50, both Bcl-3‭ ‬and p50‭ ‬were recruited to the TNF promoter, BCL3‭ ‬ and‭ ‬p50‭ ‬NFkB recruitment to‭ ‬TNF ‬promoter prevents binding of‭ ‬p65/p50‭ ‬NFkB‭ ‬heterodimers to‭ ‬TNF promotor and suppresses‭ ‬TNF ‬expression downstream of‭ ‬IL10. PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12. PMID:15465827 BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. BCL3 inhibits expression of TNF. PMID:11875494 HMOX1 (HO1) mediates IL-10-induced suppression of TNF production. PMID:16878026, PMID:14660645, PMID:15644117, PMID:10952726 Increased TNF expression downstream of HMGB1 is regulated via MYD88 and probably NFkB. PMID:10754326 Human TNF-alpha gene has binding sites for NF-kappa B. By transient transfection, NF-kappa B p65 and p50 synergistically activated the TNF-alpha promoter. Although both the kappa B1 and kappa B3 sites bound transcriptionally active NF-kappa B p50/p65 heterodimers, only the kappa B1 site contributed to down-regulation by NF-kappa B p50 homodimers. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. PMID:7594497 TGFB1 and IL10 dowregulate expression of TNF. PMID:23390297 MIF inhitits expression of M1 markers such as TNF. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4012.5" y="2548.75"/> <port id="pr_4d6d9ac5-eb9b-4ed0-95f0-c58138f8b6c6_p1" x="4017.5" y="2538.75"/> <port id="pr_4d6d9ac5-eb9b-4ed0-95f0-c58138f8b6c6_p2" x="4017.5" y="2568.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_d60f3086-af16-4bbd-9b57-8d64f9ca313f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1837.75" y="1617.1558"/> <port id="pr_d60f3086-af16-4bbd-9b57-8d64f9ca313f_p1" x="1827.75" y="1622.1558"/> <port id="pr_d60f3086-af16-4bbd-9b57-8d64f9ca313f_p2" x="1857.75" y="1622.1558"/> </glyph> <glyph class="process" orientation="vertical" id="pr_627aa741-a86c-46ff-b271-1266bace403c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22955274 MKNK1 (MNK1) regulates TNF mRNA polysome assembly and upregulates TNF translation. IL-10 Inhibits TNF translation through SHIP1-mediated Inhibition of MKNK1. PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). PMID:16878026, PMID:14660645, PMID:15644117, PMID:10952726, PMID:23508573 Increased TNF expression downstream of HMGB1 is regulated via MYD88 and probably NFkB. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4013.6494" y="2656.25"/> <port id="pr_627aa741-a86c-46ff-b271-1266bace403c_p1" x="4018.6494" y="2646.25"/> <port id="pr_627aa741-a86c-46ff-b271-1266bace403c_p2" x="4018.6494" y="2676.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c34649f5-ce2f-47af-8501-9a0239e584fe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20547845 TLR4 signaling downstream of HMGB1 induces secretion of IL10 PMID:16713974 RNAi-mediated knockdown of CREB, Fos, and Jun expression resulted in diminished TLR2-induced IL-10 production GSK3B inhitits activation (DNA binding) of AP-1 factors. JNK is a classical activator of AP1 transcription factors. Inhibition of JNK downregulates IL10 expression. Probably via AP1. PMID:17404308 CSF1 upregulates expression of IL10 and CCL2 probably via CSF1R. PMID:15749884 c-Maf binds to the −206/−171 region in the IL-10 promoter and upregulates IL10 expression. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1341.5625" y="2987.875"/> <port id="pr_c34649f5-ce2f-47af-8501-9a0239e584fe_p1" x="1346.5625" y="2977.875"/> <port id="pr_c34649f5-ce2f-47af-8501-9a0239e584fe_p2" x="1346.5625" y="3007.875"/> </glyph> <glyph class="process" orientation="vertical" id="pr_174c5be1-055a-403c-9751-f90f59fdf7e8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:21115385,PMID:10433356 IL10‭ ‬acts via IL10‭ ‬receptor. IL10‭ ‬first binds to IL10RA The IL10/IL10R1A ‬interaction changes the cytokine conformation allowing the association of the IL10/IL10RA ‬complex with IL10RB. PMID:‭15833879 ‭Anti IL-10 receptor–specific antibody switched TAMs from an M2 to an M1 macrophage–like phenotype. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="567.0" y="1338.0"/> <port id="pr_174c5be1-055a-403c-9751-f90f59fdf7e8_p1" x="572.0" y="1358.0"/> <port id="pr_174c5be1-055a-403c-9751-f90f59fdf7e8_p2" x="572.0" y="1328.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_99849343-23b9-477e-a16b-427681ebaae8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates JAK1 Two tyrosines‭ (‬Tyr‭ ‬446‭ ‬and Tyr‭ ‬496‭) ‬of IL-10RA are phosphorylated by the JAK1,‭ ‬to which the transcription factor STAT3‭ ‬binds via its SH2‭ ‬domain and in turn becomes itself phosphorylated References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="927.625" y="1090.75"/> <port id="pr_99849343-23b9-477e-a16b-427681ebaae8_p1" x="917.625" y="1095.75"/> <port id="pr_99849343-23b9-477e-a16b-427681ebaae8_p2" x="947.625" y="1095.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_41145b05-5026-4260-b39a-4bfc25608687"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1165.0" y="1915.0"/> <port id="pr_41145b05-5026-4260-b39a-4bfc25608687_p1" x="1170.0" y="1905.0"/> <port id="pr_41145b05-5026-4260-b39a-4bfc25608687_p2" x="1170.0" y="1935.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2f89da8c-36ed-481d-90d4-855545c9c661"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15465827 BCL3 forms complex with HDAC1 and repression of the TNF promoter by BCL3 requires Histone Deacetylase Activity. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4155.6396" y="2255.5"/> <port id="pr_2f89da8c-36ed-481d-90d4-855545c9c661_p1" x="4160.6396" y="2275.5"/> <port id="pr_2f89da8c-36ed-481d-90d4-855545c9c661_p2" x="4160.6396" y="2245.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3fcd1c51-4a1f-4153-a39c-4810dac47cc0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16713974 Production of IL10 is partially ERK dependent. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1344.6875" y="3091.0"/> <port id="pr_3fcd1c51-4a1f-4153-a39c-4810dac47cc0_p1" x="1349.6875" y="3081.0"/> <port id="pr_3fcd1c51-4a1f-4153-a39c-4810dac47cc0_p2" x="1349.6875" y="3111.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_600674ce-05e9-4c3e-bce5-2193a6aa2022"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1A. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4841.25" y="2541.0"/> <port id="pr_600674ce-05e9-4c3e-bce5-2193a6aa2022_p1" x="4846.25" y="2531.0"/> <port id="pr_600674ce-05e9-4c3e-bce5-2193a6aa2022_p2" x="4846.25" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d513451c-473d-45f4-ab6e-be11fb818e90"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20547845 TLR4 signaling downstream of HMGB1 induces secretion of IL10 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="833.4375" y="2152.5"/> <port id="pr_d513451c-473d-45f4-ab6e-be11fb818e90_p1" x="838.4375" y="2172.5"/> <port id="pr_d513451c-473d-45f4-ab6e-be11fb818e90_p2" x="838.4375" y="2142.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_726e4541-e9ff-41e1-897d-b09632087dcc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15465827 BCL3 inhibits expression of IL1B. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4923.125" y="2541.0"/> <port id="pr_726e4541-e9ff-41e1-897d-b09632087dcc_p1" x="4928.125" y="2531.0"/> <port id="pr_726e4541-e9ff-41e1-897d-b09632087dcc_p2" x="4928.125" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_89a1aa62-51c6-46d3-9003-14506a4c935a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IL1A Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:10952726 HMGB1 induces expression of proinflammotory cytokine IL1A References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4836.875" y="2629.75"/> <port id="pr_89a1aa62-51c6-46d3-9003-14506a4c935a_p1" x="4841.875" y="2619.75"/> <port id="pr_89a1aa62-51c6-46d3-9003-14506a4c935a_p2" x="4841.875" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_34746d82-4f56-4297-a6f7-5bc4141997fc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20547845, PMID:10952726 TLR4 signaling downstream of HMGB1 induces secretion of IL1B probably via NFkB References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4925.0" y="2629.75"/> <port id="pr_34746d82-4f56-4297-a6f7-5bc4141997fc_p1" x="4930.0" y="2619.75"/> <port id="pr_34746d82-4f56-4297-a6f7-5bc4141997fc_p2" x="4930.0" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9a8b904b-48b3-477f-9ac4-bb5b6971323d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12907458 IL10 induces SOCS3 expression in STAT3 dependent manner. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3295.0" y="855.0"/> <port id="pr_9a8b904b-48b3-477f-9ac4-bb5b6971323d_p1" x="3300.0" y="875.0"/> <port id="pr_9a8b904b-48b3-477f-9ac4-bb5b6971323d_p2" x="3300.0" y="845.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1ee8fd7b-4311-4586-a540-51bba9162c4f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4653.875" y="2629.75"/> <port id="pr_1ee8fd7b-4311-4586-a540-51bba9162c4f_p1" x="4658.875" y="2619.75"/> <port id="pr_1ee8fd7b-4311-4586-a540-51bba9162c4f_p2" x="4658.875" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_28a99bb4-03eb-455f-a07d-06617e19785c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3306.25" y="773.75"/> <port id="pr_28a99bb4-03eb-455f-a07d-06617e19785c_p1" x="3311.25" y="793.75"/> <port id="pr_28a99bb4-03eb-455f-a07d-06617e19785c_p2" x="3311.25" y="763.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b9758761-7d96-4414-9748-3ff6805d401f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17485448 IL10‭ ‬upregulates expression of‭ ‬TNIP3 (ABIN3). References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3456.5" y="968.0"/> <port id="pr_b9758761-7d96-4414-9748-3ff6805d401f_p1" x="3461.5" y="958.0"/> <port id="pr_b9758761-7d96-4414-9748-3ff6805d401f_p2" x="3461.5" y="988.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_fbc605d1-5a06-424c-bd12-ad8b99876370"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3527.5" y="992.41077"/> <port id="pr_fbc605d1-5a06-424c-bd12-ad8b99876370_p1" x="3517.5" y="997.41077"/> <port id="pr_fbc605d1-5a06-424c-bd12-ad8b99876370_p2" x="3547.5" y="997.41077"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c9ad9d65-796a-4af3-aa14-a9a9e20f840d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15145317 The activated IKK complex, predominantly acting through IKKb in an IKKg-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. PMID:17485448, PMID:10542212 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1.. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3753.25" y="1593.25"/> <port id="pr_c9ad9d65-796a-4af3-aa14-a9a9e20f840d_p1" x="3773.25" y="1598.25"/> <port id="pr_c9ad9d65-796a-4af3-aa14-a9a9e20f840d_p2" x="3743.25" y="1598.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_81b687ab-7fab-4be1-87d6-02e9d063b5e6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15145317 The activated IKK complex catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3589.3096" y="1704.25"/> <port id="pr_81b687ab-7fab-4be1-87d6-02e9d063b5e6_p1" x="3594.3096" y="1694.25"/> <port id="pr_81b687ab-7fab-4be1-87d6-02e9d063b5e6_p2" x="3594.3096" y="1724.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9e6f88e3-2c15-4e41-b72e-adc1ca8a53e0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17485448 TNIP3 (ABIN3‭) ‬inhibits IKK complex trough direct binding to IKBKG.. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3619.75" y="1183.772"/> <port id="pr_9e6f88e3-2c15-4e41-b72e-adc1ca8a53e0_p1" x="3609.75" y="1188.772"/> <port id="pr_9e6f88e3-2c15-4e41-b72e-adc1ca8a53e0_p2" x="3639.75" y="1188.772"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5c92be2d-1dc3-4a7a-b622-0d0bd084d485"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10542212 IL10‭ ‬inhibits TNF-dependent‭ ‬IL8‭ ‬and IKBa‭ ‬expression in‭ ‬NFkB dependent manner. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3921.875" y="1902.5"/> <port id="pr_5c92be2d-1dc3-4a7a-b622-0d0bd084d485_p1" x="3926.875" y="1922.5"/> <port id="pr_5c92be2d-1dc3-4a7a-b622-0d0bd084d485_p2" x="3926.875" y="1892.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e0323557-868c-428a-9a45-2c12a5af8af6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3927.5" y="1839.5"/> <port id="pr_e0323557-868c-428a-9a45-2c12a5af8af6_p1" x="3932.5" y="1859.5"/> <port id="pr_e0323557-868c-428a-9a45-2c12a5af8af6_p2" x="3932.5" y="1829.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_08d09476-4978-4517-b6ca-90ec1985a9a4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3906.4326" y="1710.0"/> <port id="pr_08d09476-4978-4517-b6ca-90ec1985a9a4_p1" x="3911.4326" y="1730.0"/> <port id="pr_08d09476-4978-4517-b6ca-90ec1985a9a4_p2" x="3911.4326" y="1700.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_408e57e2-69fc-4ba0-bf77-dc6f56156c2d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16878026, PMID:10952726 HMGB1 induces IL8 secretion probably via NFkB. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4563.875" y="2629.75"/> <port id="pr_408e57e2-69fc-4ba0-bf77-dc6f56156c2d_p1" x="4568.875" y="2619.75"/> <port id="pr_408e57e2-69fc-4ba0-bf77-dc6f56156c2d_p2" x="4568.875" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8decec85-f14d-465f-b2fa-a6607ebbb36d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20547845, PMID:10952726 TLR4 signaling downstream of HMGB1 induces secretion of IL6 probably via NFkB References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4471.0" y="2629.75"/> <port id="pr_8decec85-f14d-465f-b2fa-a6607ebbb36d_p1" x="4476.0" y="2619.75"/> <port id="pr_8decec85-f14d-465f-b2fa-a6607ebbb36d_p2" x="4476.0" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_04066dbf-2162-4029-83ce-352ff5391ff0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. PMID:23390297 MIF inhitits expression of M1 markers such as IL12p40 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4658.25" y="2541.0"/> <port id="pr_04066dbf-2162-4029-83ce-352ff5391ff0_p1" x="4663.25" y="2531.0"/> <port id="pr_04066dbf-2162-4029-83ce-352ff5391ff0_p2" x="4663.25" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5ec72694-88d6-4621-9fb4-04f819b08724"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4568.25" y="2541.0"/> <port id="pr_5ec72694-88d6-4621-9fb4-04f819b08724_p1" x="4573.25" y="2531.0"/> <port id="pr_5ec72694-88d6-4621-9fb4-04f819b08724_p2" x="4573.25" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_978c34a0-9c53-48a1-b7f2-bc9f07c7b6da"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17485448 Inhibition of‭ ‬NFkB signaling downstream of‭ ‬ABIN3‭ ‬ inhibits expression of‭ ‬IL8,‭ ‬IL6,‭ ‬TNF,‭ ‬IL12 PMID:15749903, PMID:16413922 NFKBID (IkBNS) interacts with NFkB p50 inhibit recrutement NFkB p50/p65 to IL-6 promoter and inhibit IL6 expression. PMID:9743347 IL-13 blocks NF-κB-dependent production of IL6 PMID:16243976 IRF4 downregulates expression of TNFa, IL12p40, IL6 probably via inhibition of NF-kB and JNK signaling pathways. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4471.0" y="2541.0"/> <port id="pr_978c34a0-9c53-48a1-b7f2-bc9f07c7b6da_p1" x="4476.0" y="2531.0"/> <port id="pr_978c34a0-9c53-48a1-b7f2-bc9f07c7b6da_p2" x="4476.0" y="2561.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6deb48de-f425-46be-8295-a6664e6d0c65"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12907458, PMID:12193690 IL10 upregulates expression of IL4RA in STAT3 dependent manner. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1180.0" y="2135.0"/> <port id="pr_6deb48de-f425-46be-8295-a6664e6d0c65_p1" x="1200.0" y="2140.0"/> <port id="pr_6deb48de-f425-46be-8295-a6664e6d0c65_p2" x="1170.0" y="2140.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_ff9d76d5-4cbb-4246-9ab7-55a5a154189f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="657.5" y="2071.8965"/> <port id="pr_ff9d76d5-4cbb-4246-9ab7-55a5a154189f_p1" x="677.5" y="2076.8965"/> <port id="pr_ff9d76d5-4cbb-4246-9ab7-55a5a154189f_p2" x="647.5" y="2076.8965"/> </glyph> <glyph class="process" orientation="vertical" id="pr_ba8df2d1-5c90-4aa7-868e-f6b6e641bac8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11875494 IL10 stimulates HMOX1 (HO1) expression via MAPK p38 stimulation. IL-10-mediated increase in HMOX1 mRNA level was completely blocked by SB203580, a specific inhibitor of p38. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3915.5" y="2182.0"/> <port id="pr_ba8df2d1-5c90-4aa7-868e-f6b6e641bac8_p1" x="3920.5" y="2172.0"/> <port id="pr_ba8df2d1-5c90-4aa7-868e-f6b6e641bac8_p2" x="3920.5" y="2202.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3c95d3d9-7e59-4e2c-b433-c2e61d73708b"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3316.0" y="593.6513"/> <port id="pr_3c95d3d9-7e59-4e2c-b433-c2e61d73708b_p1" x="3306.0" y="598.6513"/> <port id="pr_3c95d3d9-7e59-4e2c-b433-c2e61d73708b_p2" x="3336.0" y="598.6513"/> </glyph> <glyph class="process" orientation="vertical" id="pr_80b14e44-5f5f-4408-8dc8-88fb09714bf0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11875494 IL10-induced p38 phosphorylation. PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. PMID:10925299 IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation downstream of IL13. PMID:23508573 HMGB1 induces activation (phosphorylation) of p38 via TLR4. PMID:12811837, PMID:16713974 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3640.0" y="2163.5"/> <port id="pr_80b14e44-5f5f-4408-8dc8-88fb09714bf0_p1" x="3645.0" y="2153.5"/> <port id="pr_80b14e44-5f5f-4408-8dc8-88fb09714bf0_p2" x="3645.0" y="2183.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_722b0d9b-6cf9-4be1-9c56-48293bf166fe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3921.0312" y="2243.25"/> <port id="pr_722b0d9b-6cf9-4be1-9c56-48293bf166fe_p1" x="3926.0312" y="2233.25"/> <port id="pr_722b0d9b-6cf9-4be1-9c56-48293bf166fe_p2" x="3926.0312" y="2263.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_426842e5-8b4f-4e2c-a3a1-2f3227add10f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11875494 HMOX1 (HO1) mediates the inhibitory effect of IL10 on LPS-induced NOS2 (INOS) expression. PMID:6357187, PMID:8871614 IL13 downregulates INOS activity via ILRA1/STAT6 pathway. PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses NF-kB dependent expression NOS2, Ccl3, Ccl7, Cxcl10. PMID:15644117, PMID:17260466 HMGB1 induces NO production probably via NFkB dependent upregulation of INOS expression. PMID:17689680 STAT1 binds to INOS promoter and induces INOS expression and NO production downstream of IFNG in murine macrophages. Acetylation inhibits STAT1 binding to promotor. PMID:11399519 STAT1, IRF1 and NF-kB interact with NOS2 promoter and cooperatively activate NOS2 expression in macrophages downstteam of IFNG. PMID:23390297 MIF inhitits expression of M1 markers such as NOS2 (INOS). PMID;PMID:20194441 HIF1 upregulates expression of INOS. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3854.1875" y="3108.75"/> <port id="pr_426842e5-8b4f-4e2c-a3a1-2f3227add10f_p1" x="3859.1875" y="3098.75"/> <port id="pr_426842e5-8b4f-4e2c-a3a1-2f3227add10f_p2" x="3859.1875" y="3128.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_93755347-ccc6-452a-bea5-b658b4304ac7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14568929, PMID:10925299 IL13 induces arginase activity which results in L-arginin deficiency. L-arginin deficiency impairs iNOS protein synthesis and stability. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3853.3894" y="3201.25"/> <port id="pr_93755347-ccc6-452a-bea5-b658b4304ac7_p1" x="3858.3894" y="3191.25"/> <port id="pr_93755347-ccc6-452a-bea5-b658b4304ac7_p2" x="3858.3894" y="3221.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2c7cc99e-0110-400b-9fda-27fc395c3102"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11875494 HMOX1 (HO1) mediates IL-10-induced suppression of MMP9 expression. PMID:23390297, PMID:22461508 MIF signaling induces angiogenesis provavly via upregulation of MMP9, VEGF expression. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2083.125" y="3360.0"/> <port id="pr_2c7cc99e-0110-400b-9fda-27fc395c3102_p1" x="2088.125" y="3350.0"/> <port id="pr_2c7cc99e-0110-400b-9fda-27fc395c3102_p2" x="2088.125" y="3380.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5db2ea5f-fd4e-488d-830f-8d1e5839a7c8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2085.0" y="3431.25"/> <port id="pr_5db2ea5f-fd4e-488d-830f-8d1e5839a7c8_p1" x="2090.0" y="3421.25"/> <port id="pr_5db2ea5f-fd4e-488d-830f-8d1e5839a7c8_p2" x="2090.0" y="3451.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3d1a39c4-225a-45c1-9766-6034ea8189b7"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5018.0" y="2541.0"/> <port id="pr_3d1a39c4-225a-45c1-9766-6034ea8189b7_p1" x="5023.0" y="2531.0"/> <port id="pr_3d1a39c4-225a-45c1-9766-6034ea8189b7_p2" x="5023.0" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f5e210f1-cea6-488b-8b26-cc678e9e594a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:15749903 NFKBID (IkBNS) expression is induced by IL-10. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1350.0" y="1505.0"/> <port id="pr_331c64ac-1af4-4c37-8cd8-da781f5c04f7_p1" x="1340.0" y="1510.0"/> <port id="pr_331c64ac-1af4-4c37-8cd8-da781f5c04f7_p2" x="1370.0" y="1510.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_c96bd85c-359b-4bbd-9af5-3e0b7168ffee"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2943.9517" y="1738.75"/> <port id="pr_c96bd85c-359b-4bbd-9af5-3e0b7168ffee_p1" x="2933.9517" y="1743.75"/> <port id="pr_c96bd85c-359b-4bbd-9af5-3e0b7168ffee_p2" x="2963.9517" y="1743.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_453cea09-6e9b-4d8d-a2da-424ac0ddef41"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16413922 NFKBID (IkBNS) inhibit late phase (after 3h) of expression of proinflanotory cytokines Il-12p40 (IL-12p40), Il-18 (IL-18) and Csf3 (G_CSF). References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5108.125" y="2541.0"/> <port id="pr_453cea09-6e9b-4d8d-a2da-424ac0ddef41_p1" x="5113.125" y="2531.0"/> <port id="pr_453cea09-6e9b-4d8d-a2da-424ac0ddef41_p2" x="5113.125" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_b41a3332-64a6-4037-98af-7704f5904bd5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:22955274 SHIP1 inhibit MAPKp38 activation and prevent MKNK1 (MNK1) phosphorylation by inhibiting the p38 MAPK pathway downstream of IL10. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3775.0" y="2215.0"/> <port id="pr_b41a3332-64a6-4037-98af-7704f5904bd5_p1" x="3780.0" y="2205.0"/> <port id="pr_b41a3332-64a6-4037-98af-7704f5904bd5_p2" x="3780.0" y="2235.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b7dac7a3-8cec-4c6a-b6e0-87316c1edc0f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20435894 3′-UTR of SHIP1 is targeted by miR-155. Inhibition of Mir155 expression upregulates SHIP downstream of IL10. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2815.0" y="1649.8345"/> <port id="pr_b7dac7a3-8cec-4c6a-b6e0-87316c1edc0f_p1" x="2805.0" y="1654.8345"/> <port id="pr_b7dac7a3-8cec-4c6a-b6e0-87316c1edc0f_p2" x="2835.0" y="1654.8345"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5e0e9692-c0a5-4c49-b070-71db925f30ab"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5110.0" y="2629.75"/> <port id="pr_5e0e9692-c0a5-4c49-b070-71db925f30ab_p1" x="5115.0" y="2619.75"/> <port id="pr_5e0e9692-c0a5-4c49-b070-71db925f30ab_p2" x="5115.0" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e890988a-af46-4931-bdf5-81944799996f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4745.5" y="2541.0"/> <port id="pr_e890988a-af46-4931-bdf5-81944799996f_p1" x="4750.5" y="2531.0"/> <port id="pr_e890988a-af46-4931-bdf5-81944799996f_p2" x="4750.5" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_19286ec6-ca2d-447e-a865-b7f4b7fe536a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17404308 CSF2 have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4745.5" y="2629.75"/> <port id="pr_19286ec6-ca2d-447e-a865-b7f4b7fe536a_p1" x="4750.5" y="2619.75"/> <port id="pr_19286ec6-ca2d-447e-a865-b7f4b7fe536a_p2" x="4750.5" y="2649.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d56a3246-e7b4-4a9b-991a-563aac885fe9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12193690 Up-regulation of IL4RA by IL10 correlates with increased IL4-dependent expression of arginase-1 (ARG1). PMID:10925299, PMID:6357187 IL-13 induces de novo synthesis of arginase I mRNA and protein. Probably via STAT6. PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. 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</body> </html> </notes> <bbox w="10.0" h="10.0" x="2725.1362" y="3157.25"/> <port id="pr_208dc8d7-43f5-44de-a00a-d45b87de150c_p1" x="2730.1362" y="3147.25"/> <port id="pr_208dc8d7-43f5-44de-a00a-d45b87de150c_p2" x="2730.1362" y="3177.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d3e8e1af-7554-4542-833b-7945c1ed8aef"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4000.375" y="3878.625"/> <port id="pr_d3e8e1af-7554-4542-833b-7945c1ed8aef_p1" x="4005.375" y="3868.625"/> <port id="pr_d3e8e1af-7554-4542-833b-7945c1ed8aef_p2" x="4005.375" y="3898.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_187ff036-9d57-4bf0-943e-c6adf6e58059"> <notes> <html 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IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. PMID:21372296 HMGB1 markedly increased the expression of the genes for VEGF, and TGFB1 in peritoneal macrophages via TLR4-dependent mechanisms. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3478.0625" y="2512.625"/> <port id="pr_fa12d9b8-ca61-4344-a5ff-741ee0cad820_p1" x="3483.0625" y="2502.625"/> <port id="pr_fa12d9b8-ca61-4344-a5ff-741ee0cad820_p2" x="3483.0625" y="2532.625"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_2c6344d3-6cf2-4b97-98fa-f5835710b68f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16878026, PMID:14660645 Increased TNF secretion downstream of HMGB1 is regulated via MYD88 and probably NFkB. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5215.0" y="2319.2017"/> <port id="pr_2c6344d3-6cf2-4b97-98fa-f5835710b68f_p1" x="5205.0" y="2324.2017"/> <port id="pr_2c6344d3-6cf2-4b97-98fa-f5835710b68f_p2" x="5235.0" y="2324.2017"/> </glyph> <glyph class="process" orientation="vertical" id="pr_45275a9b-1109-4047-97ec-c59e2d1d5d99"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16327802 IL13 and TNF inducese TGFB1 expression via AP-1 transcription factors.IL13 induces binding of c-jun and fra2 ti TGFB1 promotor, and TNF binding of c-jun, JunD and c-fos. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3366.5625" y="2512.625"/> <port id="pr_45275a9b-1109-4047-97ec-c59e2d1d5d99_p1" x="3371.5625" y="2502.625"/> <port id="pr_45275a9b-1109-4047-97ec-c59e2d1d5d99_p2" x="3371.5625" y="2532.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_34bdce81-0959-466d-9d61-89990be9d400"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3087.5625" y="2514.625"/> <port id="pr_34bdce81-0959-466d-9d61-89990be9d400_p1" x="3092.5625" y="2504.625"/> <port id="pr_34bdce81-0959-466d-9d61-89990be9d400_p2" x="3092.5625" y="2534.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_37b3350c-2dff-4a77-ae7b-dceb7dcf803f"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3221.0625" y="2512.625"/> <port id="pr_37b3350c-2dff-4a77-ae7b-dceb7dcf803f_p1" x="3226.0625" y="2502.625"/> <port id="pr_37b3350c-2dff-4a77-ae7b-dceb7dcf803f_p2" x="3226.0625" y="2532.625"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bb06c76f-2077-4811-94ab-660d65d6c0f2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:14610620, PMID:12223527 IL13 acts via IL4 receptor type 2, which contains two subunits IL4R and IL13RA1 PMID:14610620, PMID:12223527, PMID:20510870 JAK1 associated with IL4R and JAK2 or TYK associated with IL13RA1 participate in signal transduction; They phosphorylate the second, third, or fourth tyrosine residues of the IL-4Ra cytoplasmic domain. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2025.0" y="3003.25"/> <port id="pr_31602039-e42b-482d-a23b-956ec57f7fdd_p1" x="2030.0" y="2993.25"/> <port id="pr_31602039-e42b-482d-a23b-956ec57f7fdd_p2" x="2030.0" y="3023.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_3a32fbe4-867d-4b37-85a9-fa56724218ad"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:7890616 Intracellular Ca2+ release induces cAMP Accumulation in Human Monocytes and activation of PKA signaling downstream of IL13. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1904.125" y="2990.25"/> <port id="pr_3a32fbe4-867d-4b37-85a9-fa56724218ad_p1" x="1894.125" y="2995.25"/> <port id="pr_3a32fbe4-867d-4b37-85a9-fa56724218ad_p2" x="1924.125" y="2995.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d6409ebb-ef11-4736-9ecc-bcaab214a432"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1779.8237" y="2851.25"/> <port id="pr_d6409ebb-ef11-4736-9ecc-bcaab214a432_p1" x="1784.8237" y="2841.25"/> <port id="pr_d6409ebb-ef11-4736-9ecc-bcaab214a432_p2" x="1784.8237" y="2871.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_324abc7f-66cc-4ab7-9e36-f56e4d68896d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1687.0404" y="2706.4907"/> <port id="pr_324abc7f-66cc-4ab7-9e36-f56e4d68896d_p1" x="1692.0404" y="2696.4907"/> <port id="pr_324abc7f-66cc-4ab7-9e36-f56e4d68896d_p2" x="1692.0404" y="2726.4907"/> </glyph> <glyph class="process" orientation="vertical" id="pr_aa92f8d5-2761-4b9b-9b82-15a7b2f5ebc3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 PMID:7890616 PCL (probably PCLG1) induces t hydrolysis of phosphoinositides and activates InsP3-induced intracellular Ca2+ release downstream of IL13. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1574.25" y="2660.0"/> <port id="pr_aa92f8d5-2761-4b9b-9b82-15a7b2f5ebc3_p1" x="1579.25" y="2650.0"/> <port id="pr_aa92f8d5-2761-4b9b-9b82-15a7b2f5ebc3_p2" x="1579.25" y="2680.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_6b3429fe-312c-4e6d-882c-74a24acf6679"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: HUGO:IRS2 Identifiers_end Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:9535722 IL13 induces phosporylation of IRS2 and PLCG1 which is probably a PLC responsible for downstream IL13 dependent Ca2+ mobilization signaling and assosiation of IRS2 and PLCG1 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1539.1422" y="2708.0337"/> <port id="pr_6b3429fe-312c-4e6d-882c-74a24acf6679_p1" x="1559.1422" y="2713.0337"/> <port id="pr_6b3429fe-312c-4e6d-882c-74a24acf6679_p2" x="1529.1422" y="2713.0337"/> </glyph> <glyph class="process" orientation="vertical" id="pr_00d4e8b2-9cb8-4178-903d-1a346e78452d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8871614 IL13 induces MHC classé expression via STAT6 pathway PMID:7902377, PMID:1655948 IL-10 down-regulates not only the constitutive class 2 MHC Agexpression on mono- cytes , but also inhibites strongly the IL-13-induced class I1 MHC expression. PMID:23390297 MIF inhitits expression of M1 markers such as class 2 MHC. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5225.75" y="2976.0"/> <port id="pr_00d4e8b2-9cb8-4178-903d-1a346e78452d_p1" x="5230.75" y="2966.0"/> <port id="pr_00d4e8b2-9cb8-4178-903d-1a346e78452d_p2" x="5230.75" y="2996.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0cf1a289-16ff-4f34-8f49-52669eeaa9d9"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16243976 INFG upregulates surface expression of MHC II. IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 resulted in increased surface expression of MHC II. PMID:15644117 HMGB1 upregulates the expression of MHC class II molecules on the surface of macrophages. PMID:12928384 CSF2 (GM-CSF) increases surface class II MHC and costimulatory molecule expression in primary human monocytes without evidence of differentiation. PMID:8871614 IL13 induces MHC classe II expression via STAT6 pathway References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5274.89" y="3078.0"/> <port id="pr_0cf1a289-16ff-4f34-8f49-52669eeaa9d9_p1" x="5279.89" y="3068.0"/> <port id="pr_0cf1a289-16ff-4f34-8f49-52669eeaa9d9_p2" x="5279.89" y="3098.0"/> </glyph> <glyph class="and" orientation="vertical" id="logicglyph_f901309a-7aff-4f8d-8e69-b081be00245e"> <bbox w="20.0" h="20.0" x="5128.139" y="1951.7234"/> <port id="logicglyph_f901309a-7aff-4f8d-8e69-b081be00245e_p1" x="5138.139" y="1941.7234"/> <port id="logicglyph_f901309a-7aff-4f8d-8e69-b081be00245e_p2" x="5138.139" y="1981.7234"/> </glyph> <glyph class="process" orientation="vertical" id="pr_544900f3-faab-4d6b-8e5a-18836e1839ef"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="703.25" y="2069.5"/> <port id="pr_544900f3-faab-4d6b-8e5a-18836e1839ef_p1" x="708.25" y="2059.5"/> <port id="pr_544900f3-faab-4d6b-8e5a-18836e1839ef_p2" x="708.25" y="2089.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_e443602e-6bd7-4e93-b3aa-24b95de6a49d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23124025 Tyk2 but not Jak2 is involved in regulating the IL-13-stimulated activation of Stat1(TYR701) PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1210.625" y="2294.5"/> <port id="pr_e443602e-6bd7-4e93-b3aa-24b95de6a49d_p1" x="1200.625" y="2299.5"/> <port id="pr_e443602e-6bd7-4e93-b3aa-24b95de6a49d_p2" x="1230.625" y="2299.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_309497ff-ffb5-4d24-87d5-97bd485c05b2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23124025 IL13 induces expression of MAOA and ALOX15 via JAK1, TYK2, STAT1 STAT3 and STAT6. IL4 induces expression of MAOA and ALOX15 via JAK1, STAT3 and STAT6. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2935.0" y="3570.5024"/> <port id="pr_b3eaa51f-1548-424a-b666-70870e7a25e5_p1" x="2940.0" y="3560.5024"/> <port id="pr_b3eaa51f-1548-424a-b666-70870e7a25e5_p2" x="2940.0" y="3590.5024"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c1fc0cc6-f2ec-4058-b6f0-446a9fa18a34"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2935.0" y="3631.0024"/> <port id="pr_c1fc0cc6-f2ec-4058-b6f0-446a9fa18a34_p1" x="2940.0" y="3621.0024"/> <port id="pr_c1fc0cc6-f2ec-4058-b6f0-446a9fa18a34_p2" x="2940.0" y="3651.0024"/> </glyph> <glyph class="process" orientation="vertical" id="pr_00e3d85e-f0a8-43a8-8b95-7db08af05c78"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23124025 IL13 induces DUSP1 expression via TYK2 and probably STAT6 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1297.5" y="2492.5024"/> <port id="pr_00e3d85e-f0a8-43a8-8b95-7db08af05c78_p1" x="1302.5" y="2482.5024"/> <port id="pr_00e3d85e-f0a8-43a8-8b95-7db08af05c78_p2" x="1302.5" y="2512.5024"/> </glyph> <glyph class="process" orientation="vertical" id="pr_064dfaed-b75a-4e02-b70f-36898652e991"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10432118 ALOX15 activation results in induction of CD36 expression downstream of IL4 and IL13 via PRARG CD36 gene expression is directly controlled by 15-LO expression/activity in IL-13-driven monocytes/macrophages PMID:17681149 STAT6 and PPARγ together upregulate CD36 transcription. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2233.5" y="3332.6887"/> <port id="pr_064dfaed-b75a-4e02-b70f-36898652e991_p1" x="2238.5" y="3322.6887"/> <port id="pr_064dfaed-b75a-4e02-b70f-36898652e991_p2" x="2238.5" y="3352.6887"/> </glyph> <glyph class="process" orientation="vertical" id="pr_83d09bea-9b15-4c9d-a0e9-d27fcf67da03"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2233.391" y="3392.3762"/> <port id="pr_83d09bea-9b15-4c9d-a0e9-d27fcf67da03_p1" x="2238.391" y="3382.3762"/> <port id="pr_83d09bea-9b15-4c9d-a0e9-d27fcf67da03_p2" x="2238.391" y="3412.3762"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7a7088aa-0339-4bdb-9631-131291131fb6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1297.5" y="2553.0024"/> <port id="pr_7a7088aa-0339-4bdb-9631-131291131fb6_p1" x="1302.5" y="2543.0024"/> <port id="pr_7a7088aa-0339-4bdb-9631-131291131fb6_p2" x="1302.5" y="2573.0024"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9abf3b7f-cac5-4347-8068-dc4e82e1cbd0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23124025 IL4 induces expression of TIMP3 via JAK1 pathway References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1395.0" y="2495.0"/> <port id="pr_9abf3b7f-cac5-4347-8068-dc4e82e1cbd0_p1" x="1400.0" y="2485.0"/> <port id="pr_9abf3b7f-cac5-4347-8068-dc4e82e1cbd0_p2" x="1400.0" y="2515.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3bc6805a-ddce-4836-8ac0-ef0a815aa126"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1395.0" y="2552.25"/> <port id="pr_3bc6805a-ddce-4836-8ac0-ef0a815aa126_p1" x="1400.0" y="2542.25"/> <port id="pr_3bc6805a-ddce-4836-8ac0-ef0a815aa126_p2" x="1400.0" y="2572.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_730747ee-c0b1-4ff8-b52e-d5abc865d583"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10432118 Linoleic acid is oxygenated by ALOX15 to 13-HODE which activates PPARG. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1977.5" y="2059.25"/> <port id="pr_730747ee-c0b1-4ff8-b52e-d5abc865d583_p1" x="1982.5" y="2049.25"/> <port id="pr_730747ee-c0b1-4ff8-b52e-d5abc865d583_p2" x="1982.5" y="2079.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_fc0d3588-ad46-4b33-87a2-3245b12d549d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10432118 Linoleic acid is oxygenated by ALOX15 to 13-HODE which activates PPARG. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1865.0" y="2020.0"/> <port id="pr_fc0d3588-ad46-4b33-87a2-3245b12d549d_p1" x="1870.0" y="2010.0"/> <port id="pr_fc0d3588-ad46-4b33-87a2-3245b12d549d_p2" x="1870.0" y="2040.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_97aaafdd-a926-4d9a-b47f-9a151a1b5014"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10432118, PMID:21093321 IL4 upregulates expression of PPARG via JAK3/STAT6 pathway References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1965.0" y="1915.0"/> <port id="pr_97aaafdd-a926-4d9a-b47f-9a151a1b5014_p1" x="1970.0" y="1905.0"/> <port id="pr_97aaafdd-a926-4d9a-b47f-9a151a1b5014_p2" x="1970.0" y="1935.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7d559f76-6d2e-4712-91b0-7194848798c0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1969.4644" y="1976.25"/> <port id="pr_7d559f76-6d2e-4712-91b0-7194848798c0_p1" x="1974.4644" y="1966.25"/> <port id="pr_7d559f76-6d2e-4712-91b0-7194848798c0_p2" x="1974.4644" y="1996.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_9f5cfb5a-f3e0-4500-b514-31b3485e51e3"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16127449 PPARG sumoilated by PIAS1/UbC9 prevents dissociation of the NCoR–HDAC3 complex fro promoters and transrepresses expression NOS2, Ccl3, Ccl7, Cxcl10 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4323.5" y="2763.5"/> <port id="pr_9f5cfb5a-f3e0-4500-b514-31b3485e51e3_p1" x="4328.5" y="2753.5"/> <port id="pr_9f5cfb5a-f3e0-4500-b514-31b3485e51e3_p2" x="4328.5" y="2783.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0bbe0727-6e58-4922-b4e5-9df55a73e717"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2338.0" y="3327.6887"/> <port id="pr_0bbe0727-6e58-4922-b4e5-9df55a73e717_p1" x="2343.0" y="3317.6887"/> <port id="pr_0bbe0727-6e58-4922-b4e5-9df55a73e717_p2" x="2343.0" y="3347.6887"/> </glyph> <glyph class="process" orientation="vertical" id="pr_2b92f545-9fba-4cb0-bb24-196afc3edf18"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2338.0" y="3387.3762"/> <port id="pr_2b92f545-9fba-4cb0-bb24-196afc3edf18_p1" x="2343.0" y="3377.3762"/> <port id="pr_2b92f545-9fba-4cb0-bb24-196afc3edf18_p2" x="2343.0" y="3407.3762"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a0d1fd54-dda6-4e96-bb62-3b05d35879e0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23390297 MIF induces expression of M2 markers ARG1, IL10, stabilin-1, MRC-1, CD23. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2431.8987" y="3332.1887"/> <port id="pr_a0d1fd54-dda6-4e96-bb62-3b05d35879e0_p1" x="2436.8987" y="3322.1887"/> <port id="pr_a0d1fd54-dda6-4e96-bb62-3b05d35879e0_p2" x="2436.8987" y="3352.1887"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6330fca2-3af1-4ee3-8d0a-4b5ec453d0d4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2431.8987" y="3391.3762"/> <port id="pr_6330fca2-3af1-4ee3-8d0a-4b5ec453d0d4_p1" x="2436.8987" y="3381.3762"/> <port id="pr_6330fca2-3af1-4ee3-8d0a-4b5ec453d0d4_p2" x="2436.8987" y="3411.3762"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f959709b-32b2-4277-85d7-890c8fa2e75d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17404308, PMI:17404308 CSF1 upregulates expression of CCL2 probably via CSF1R. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4420.0" y="2763.5"/> <port id="pr_f959709b-32b2-4277-85d7-890c8fa2e75d_p1" x="4425.0" y="2753.5"/> <port id="pr_f959709b-32b2-4277-85d7-890c8fa2e75d_p2" x="4425.0" y="2783.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_136d9899-e3fc-4dcc-871c-d048dc6f6064"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). PMID:23508573 HMGB1 induces secretion of CCL2, CCL3 and CXCL10 (IP-10) via TLR4 pathway. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4325.0" y="2814.75"/> <port id="pr_136d9899-e3fc-4dcc-871c-d048dc6f6064_p1" x="4330.0" y="2804.75"/> <port id="pr_136d9899-e3fc-4dcc-871c-d048dc6f6064_p2" x="4330.0" y="2834.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_28f07181-4afc-4ff8-aa5d-a9bd20d7e65e"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17681149 PPARG participates in inhibition of secretion of proinflammatory molecules, such as CCL-3, TNF, and MCP-1 (CCL-2). PMID:23508573 HMGB1 induces secretion of CCL2, CCL3 and CXCL10 (IP-10) via TLR4 pathway. PMID:19915063 Phosphorylated STAT1 is critical for IFN-gamma-induced (CCL2)MCP-1 production. 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<head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:23508573 HMGB1 induces secretion of CCL2, CCL3 and CXCL10 (IP-10) via TLR4 pathway. 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IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2241.0" y="2716.5"/> <port id="pr_4e4b595d-059e-40e1-a0f6-767a7f1a63cd_p1" x="2246.0" y="2706.5"/> <port id="pr_4e4b595d-059e-40e1-a0f6-767a7f1a63cd_p2" x="2246.0" y="2736.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_106647ce-45e2-4c31-834c-a74f28b27d7a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2448.6316" y="2719.5"/> <port id="pr_d10bb00d-3488-4d96-8451-215a0634b017_p1" x="2453.6316" y="2709.5"/> <port id="pr_d10bb00d-3488-4d96-8451-215a0634b017_p2" x="2453.6316" y="2739.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4ded4147-159b-428e-8811-3f35e5ef8be1"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:20580461 IRF4 regulates expression of some IL4-dependent genes. IRF4 upregulates expression of CIITA, CYP1B1, CCL24, MPP6, and downregulate expression IL1RN. 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PMID:12223527 Stat proteins 1 alpha, 3, 5A, 5B, and 6 are phosphorylated in response to IL-13. IL-4, in contrast to IL-13, induced very low levels of phosphorylation of Stats 1 and 5 and a more robust phosphorylation of Stat3 and Stat6. Jak1 is required for Stat6 (TYR641) activation in monocytes stimulated with IL-4 PMID:10485906 SOCS1 inhibits STAT6 activation downstream of IFNG and downregulates IL4 signaling pathway. PMID:21469115 PI3K signaling is involved in STAT6 activation. 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PMID:21232017, PMID:21133840, PMID:17301840 PMID:24958845, PMID:24699077 The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex downstream of TNF and upregulates IkBa degradetion. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4629.375" y="1302.25"/> <port id="pr_711daa7d-a2d1-4f4f-90e7-05f113d2f4bc_p1" x="4649.375" y="1307.25"/> <port id="pr_711daa7d-a2d1-4f4f-90e7-05f113d2f4bc_p2" x="4619.375" y="1307.25"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_87f66dc2-d16d-4031-9ef7-ac84c2252806"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4715.0" y="1410.0"/> <port id="pr_87f66dc2-d16d-4031-9ef7-ac84c2252806_p1" x="4735.0" y="1415.0"/> <port id="pr_87f66dc2-d16d-4031-9ef7-ac84c2252806_p2" x="4705.0" y="1415.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3bda0a35-57db-47db-8efd-d48012b9fce0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: TLR4 signaling downstream of HMGB1 induces secretion of CXCL2 (MIP2). 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3640.0" y="2493.5"/> <port id="pr_547b779c-e130-4bb7-8949-6775ab4bae1a_p1" x="3645.0" y="2483.5"/> <port id="pr_547b779c-e130-4bb7-8949-6775ab4bae1a_p2" x="3645.0" y="2513.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_11e0a1e4-a588-45a1-91bf-0e9e0e52ed86"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2114.8713" y="2791.75"/> <port id="pr_11e0a1e4-a588-45a1-91bf-0e9e0e52ed86_p1" x="2119.8713" y="2781.75"/> <port id="pr_11e0a1e4-a588-45a1-91bf-0e9e0e52ed86_p2" x="2119.8713" y="2811.75"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_757897fb-df8a-400d-8ef3-5bfe0863063c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="6216.5" y="1210.0"/> <port id="pr_757897fb-df8a-400d-8ef3-5bfe0863063c_p1" x="6236.5" y="1215.0"/> <port id="pr_757897fb-df8a-400d-8ef3-5bfe0863063c_p2" x="6206.5" y="1215.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_7baea720-b078-48e0-b449-b4b81f7aabea"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17525754, PMID:9202126 SOCS-1 decreases IFNG signaling via inhiviting the catalytic activity of JAKs. PMID:12811837, PMID:10485906 ,SOCS-1 overexpression resulted in a nearly complete loss of IFNG responsiveness in macrophages References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5633.25" y="1580.5303"/> <port id="pr_7baea720-b078-48e0-b449-b4b81f7aabea_p1" x="5623.25" y="1585.5303"/> <port id="pr_7baea720-b078-48e0-b449-b4b81f7aabea_p2" x="5653.25" y="1585.5303"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9c823fed-8ab8-480f-9813-af95e6c67950"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12811837 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID: PMID:19833085 STAT1 is activated downstream of IFNG by phosphorylation of tyrosine 701, translocates to the nucleus, binds to a regulatory DNA element termed gamma-activated sequence (GAS) and stimulates transcription of STAT1 target genes. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4860.0" y="1783.5"/> <port id="pr_9c823fed-8ab8-480f-9813-af95e6c67950_p1" x="4880.0" y="1788.5"/> <port id="pr_9c823fed-8ab8-480f-9813-af95e6c67950_p2" x="4850.0" y="1788.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_349355cc-ff43-46ab-90e6-b69983358e38"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17689680 STAT1 acetilation inhibits its activity in macrophages. PMID:19879327 Probably STAT1 is acetylated by CBP at the lysine residues K410 and K413. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4740.0" y="1713.5"/> <port id="pr_349355cc-ff43-46ab-90e6-b69983358e38_p1" x="4745.0" y="1733.5"/> <port id="pr_349355cc-ff43-46ab-90e6-b69983358e38_p2" x="4745.0" y="1703.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b99bd8e4-de2d-4d17-bc54-53dc9f6b54b5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19833085, PMID:15699106, PMID:12138178, PMID:12270932 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. PMID:19833085 Probably, acetylation of STAT1 on lysine residues 410 and 413 in the nucleus results in enhanced interaction with TCP45 (PTPN2) and increased dephosphorylation References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4845.0" y="1663.5"/> <port id="pr_b99bd8e4-de2d-4d17-bc54-53dc9f6b54b5_p1" x="4835.0" y="1668.5"/> <port id="pr_b99bd8e4-de2d-4d17-bc54-53dc9f6b54b5_p2" x="4865.0" y="1668.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8cda2630-d5e6-455e-815a-3a193e19a7df"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17689680 HDACs provide STAT1 deacetylation and activation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4930.0" y="1723.5"/> <port id="pr_8cda2630-d5e6-455e-815a-3a193e19a7df_p1" x="4935.0" y="1713.5"/> <port id="pr_8cda2630-d5e6-455e-815a-3a193e19a7df_p2" x="4935.0" y="1743.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bca57494-a48d-4550-b1b8-e4fc2e9233c4"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17689680 HDACs provide STAT1 deacetylation and activation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4790.0" y="1713.5"/> <port id="pr_bca57494-a48d-4550-b1b8-e4fc2e9233c4_p1" x="4795.0" y="1703.5"/> <port id="pr_bca57494-a48d-4550-b1b8-e4fc2e9233c4_p2" x="4795.0" y="1733.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_cbfb32e6-5d9d-412d-9efa-25db25ee7d5d"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:19833085, PMID:15699106, PMID:15699106, PMID:15699106 Inactivation of nuclear STAT1 occurs rapidly following binding to chromatin and activation of target gene transcription. Subsequently STAT1 is dephosphorylated by phosphatases such as PTPN2 (TCP45) and PTPN11 (SHP2), and dephosphorylated STAT1 returns to cytoplasm, where it can potentially serve as the substrate for subsequent rounds of activation and inactivation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4860.0" y="1798.5"/> <port id="pr_cbfb32e6-5d9d-412d-9efa-25db25ee7d5d_p1" x="4850.0" y="1803.5"/> <port id="pr_cbfb32e6-5d9d-412d-9efa-25db25ee7d5d_p2" x="4880.0" y="1803.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4e64f0b9-9d74-4ff9-a108-9eb9f1d24371"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4595.0" y="980.0"/> <port id="pr_4e64f0b9-9d74-4ff9-a108-9eb9f1d24371_p1" x="4600.0" y="1000.0"/> <port id="pr_4e64f0b9-9d74-4ff9-a108-9eb9f1d24371_p2" x="4600.0" y="970.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_bd53dd12-c7b8-4bd8-a436-8f0675e8c004"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:11964313 INFG upregulates expression components of TLR signaling: MD2 (LY96) and MYD88. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4685.0" y="1000.0"/> <port id="pr_bd53dd12-c7b8-4bd8-a436-8f0675e8c004_p1" x="4690.0" y="1020.0"/> <port id="pr_bd53dd12-c7b8-4bd8-a436-8f0675e8c004_p2" x="4690.0" y="990.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_141523c8-15be-4a4b-a8d0-c6ea85f264cd"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4681.3633" y="876.25"/> <port id="pr_141523c8-15be-4a4b-a8d0-c6ea85f264cd_p1" x="4686.3633" y="896.25"/> <port id="pr_141523c8-15be-4a4b-a8d0-c6ea85f264cd_p2" x="4686.3633" y="866.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_53f42879-09a3-4d1f-a6c1-f98d5e7b8934"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4722.7773" y="911.25"/> <port id="pr_53f42879-09a3-4d1f-a6c1-f98d5e7b8934_p1" x="4727.7773" y="931.25"/> <port id="pr_53f42879-09a3-4d1f-a6c1-f98d5e7b8934_p2" x="4727.7773" y="901.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3100a86a-d1ef-4f34-8152-59b14f901936"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12433365 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:18345002 TNF induces IRF1 expression both through TNFR1 and TNFR2. TNF induced IFNB expression through IRF1 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4575.0" y="1905.0"/> <port id="pr_3100a86a-d1ef-4f34-8152-59b14f901936_p1" x="4580.0" y="1895.0"/> <port id="pr_3100a86a-d1ef-4f34-8152-59b14f901936_p2" x="4580.0" y="1925.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_5b4532b4-7b97-44d3-98f1-9aeec3f46cbf"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4575.0" y="1961.25"/> <port id="pr_5b4532b4-7b97-44d3-98f1-9aeec3f46cbf_p1" x="4580.0" y="1951.25"/> <port id="pr_5b4532b4-7b97-44d3-98f1-9aeec3f46cbf_p2" x="4580.0" y="1981.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_526a8d49-76b5-4c08-b4fb-c2171492e122"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12433365, PMID:10485906 INFG induces SOCS1 expression in macrophages. PMID:10820262 Probably IFNG induces SOCS1 expressiov via IRF1 upregulation downstream of STAT1 PMID:21097505 IL13 induces SOCS1 expression. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4920.0" y="1983.5"/> <port id="pr_526a8d49-76b5-4c08-b4fb-c2171492e122_p1" x="4925.0" y="2003.5"/> <port id="pr_526a8d49-76b5-4c08-b4fb-c2171492e122_p2" x="4925.0" y="1973.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_c1c1a91a-34a3-4c5a-b633-d115da699af6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4920.3677" y="1922.25"/> <port id="pr_c1c1a91a-34a3-4c5a-b633-d115da699af6_p1" x="4925.3677" y="1942.25"/> <port id="pr_c1c1a91a-34a3-4c5a-b633-d115da699af6_p2" x="4925.3677" y="1912.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_38cd621c-4ea3-4188-933a-59d32adb30a2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:8641346 IFNG did not affect the expression of p105 transcripts but enhanced the expression of p65 mRNA. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3330.0" y="1413.5"/> <port id="pr_38cd621c-4ea3-4188-933a-59d32adb30a2_p1" x="3335.0" y="1403.5"/> <port id="pr_38cd621c-4ea3-4188-933a-59d32adb30a2_p2" x="3335.0" y="1433.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_d8861cd0-204e-41dd-945d-48decf794d94"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3331.8313" y="1488.0"/> <port id="pr_d8861cd0-204e-41dd-945d-48decf794d94_p1" x="3336.8313" y="1478.0"/> <port id="pr_d8861cd0-204e-41dd-945d-48decf794d94_p2" x="3336.8313" y="1508.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_86d6ff5e-5dde-4754-828f-fb4f312804ef"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3370.0" y="2153.5"/> <port id="pr_86d6ff5e-5dde-4754-828f-fb4f312804ef_p1" x="3375.0" y="2143.5"/> <port id="pr_86d6ff5e-5dde-4754-828f-fb4f312804ef_p2" x="3375.0" y="2173.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7f8b0782-e497-4f28-8622-7c3113242631"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="3510.0" y="2153.5"/> <port id="pr_7f8b0782-e497-4f28-8622-7c3113242631_p1" x="3515.0" y="2143.5"/> <port id="pr_7f8b0782-e497-4f28-8622-7c3113242631_p2" x="3515.0" y="2173.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_4c24910d-c11a-4491-ab13-edd9f76f5e3c"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:16713974 AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling. IFNG prevents this inactivation. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5545.0" y="2780.0"/> <port id="pr_bb65229c-5608-4564-871e-c4afbbd37cb3_p1" x="5535.0" y="2785.0"/> <port id="pr_bb65229c-5608-4564-871e-c4afbbd37cb3_p2" x="5565.0" y="2785.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_f732da32-f1f3-4066-83b9-959969fa1df2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5769.119" y="3170.625"/> <port id="pr_f732da32-f1f3-4066-83b9-959969fa1df2_p1" x="5759.119" y="3175.625"/> <port id="pr_f732da32-f1f3-4066-83b9-959969fa1df2_p2" x="5789.119" y="3175.625"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_69e87ad6-97cc-4e7f-98c0-fa62f39c6fcc"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:12193701 INFG upregulates TNFR1 expression, probably via JAK/STAT1 pathway because this expression is inhibited in presense of SOCS1. 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CSF2 upregulates expression of TNF, and have positive influence on IL12p70 (p40+p35), IL23 (p40+p19) expression, probably via induction rapid IkBa degradetion, RELA nuclear translocation and formation p65/p50 heterodimers provided induction of NFkB signaling. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5198.0" y="2541.0"/> <port id="pr_1560103b-e390-44b2-ba3c-842bffb44ab8_p1" x="5203.0" y="2531.0"/> <port id="pr_1560103b-e390-44b2-ba3c-842bffb44ab8_p2" x="5203.0" y="2561.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7123d0fb-5ae5-4e20-85af-e4c19ade5a53"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:10623817 CCR2 ligands regulates recruiting monocytes/macrophages to tumors. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2401.2546" y="326.875"/> <port id="pr_29f917f2-134c-4a0e-b975-f7c0f721eb0b_p1" x="2406.2546" y="346.875"/> <port id="pr_29f917f2-134c-4a0e-b975-f7c0f721eb0b_p2" x="2406.2546" y="316.875"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a7a818d4-9a86-48a4-8a4c-340fa5495052"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: PMID:17404308 CSF1 downregulates TNF, IL-23p19, IL-12p40 expression probably via induction of acomulation of p50 homodimer and inhibition of p65/p50 NF-kB signaling. 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