id: PW:0000515 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000515 title: interleukin-10 signaling pathway description: 'Interleukin-10 (Il-10) is a prominent member of the interleukin 10 family of cytokines which also includes interleukin 28A, 28B and 29 known as interferon type III or lambda. In addition to the mammalian proteins, several viral homologues are also known. The many biological actions of Il-10 impinge upon the release of immune mediators and antigen presentation with an overall anti-inflammatory effect; interestingly it is Il-10 and not the other members of the family that appear to promote such effects. Il10 acts primarily on monocytes/macrophages keeping a balance between the responses of T helper (Th)1 and Th2 cell. More specifically, it inhibits the release of pro-inflammatory mediators, suppressing Th1 responses while stimulating the Th2 ones. The broad spectrum of biological effects Il10 exerts, relies on the coordinated regulation of expression of hundreds of genes. Expression experiments point to ~1,600 up-regulated and ~1,300 down-regulated genes as a result of Il10 signaling which engages the Jak-Stat intracellular pathway. There are two Il10 receptors - Il10ra and Il10rb; Il10ra is primarily expressed in immune cells whereas the expression of Il10rb is ubiquitous. Unlike Il10ra which is specific for Il10, Il10rb is part of receptor complexes for other members of the interleukin-10 family. Upon binding to Il10ra, the cytokine undergoes conformational changes that facilitate the association of Il-10/Il10ra complex with Il10rb; by itself, Il10rb is unable to associate with Il10. The Il-10/Il10-receptors complex activates members of the Janus kinase family: Jak1, which associates with Il10ra and Tyk2 which associates with Il10rb. Subsequently, the kinases phosphorylate two tyrosine residues in Il10ra resulting in the recruitment of Stat3 via its SH2 ( src homology 2 ) domain followed by its own Jak-mediated phosphorylation. Stat1, and in some cell types Stat5 can also be activated in response to Il10. Activated homo- and heterodimers of Stat translocate to the nucleus to regulate the transcription of many genes, including Socs3 which binds to and inhibits the activity of Jak kinases and may mediate the termination of Il10 effects. Stat3 is also essential for the expression of Il10 downstream of pro-inflammatory cytokines such as 1l-6 and Il-12 (with other Stats also contributing). Pathogenic microorganisms can also induce Il-10 downstream of Toll-like receptors (TLR) such as Tlr2; many TLRs are targets for Il-10 mediated suppression. At times, pathogens mediate Il10 induction to use the production of selected cytokines as a virulence strategy to promote their survival within the host. Interestingly, despite intense research on the Il10 system, the molecular mechanisms underlying its many biological actions remain elusive. For instance, how does a C-terminal region achieve its crucial role in the inhibition of release of pro-inflammatory mediators or what are the roles played by other kinases which Il10 activates - are among the questions still awaiting answers.' diagram_image: https://rgd.mcw.edu/pathway/PW0000515/Interleukin-10%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000515/Interleukin-10%20signaling%20pathway/Interleukin-10%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000209 label: Jak-Stat signaling pathway diagram_gene_links: - id: RGD:2886 label: Il10 - id: RGD:620138 label: Il10ra - id: RGD:1560373 label: Il10rb - id: RGD:69056 label: Jak1 - id: RGD:3771 label: Stat1 - id: RGD:3772 label: Stat3 - id: RGD:2320469 label: Tyk2 diagram_chemicals: [] diagram_edges: - source: Il10 relation: associated_with target: Il10ra - source: Il10 relation: associated_with target: Il10rb - source: Il10 relation: positively_affects target: 'Th1 cell: Th2 cell responses; anti-inflammatory effects' - source: Il10ra relation: associated_with target: Jak1 - source: Il10ra relation: associated_with target: Stat1 - source: Il10rb relation: associated_with target: Tyk2 - source: Jak1 relation: positively_affects target: Il10ra - source: P-Tyr2 relation: associated_with target: Stat3 - source: Tyk2 relation: positively_affects target: Il10ra diagram_labels: - Il10 --+> Stat1 - Il10 --+> Stat3 - Il10ra --+> Jak1 - Il10rb --+> Tyk2 - P-Tyr1 - P-Tyr2 - 'Th1 cell: Th2 cell responses; anti-inflammatory effects' references: - id: RGD:5688379 citation: 'Sabat R, etal., Cytokine Growth Factor Rev. 2010 Oct;21(5):331-44. doi: 10.1016/j.cytogfr.2010.09.002. Epub 2010 Nov 5.' - id: RGD:6478705 citation: Zdanov A Cytokine Growth Factor Rev. 2010 Oct;21(5):325-30. Epub 2010 Sep 16. - id: RGD:6478706 citation: 'Sabat R, Cytokine Growth Factor Rev. 2010 Oct;21(5):315-24. doi: 10.1016/j.cytogfr.2010.11.001.' - id: RGD:6478707 citation: Couper KN, etal., J Immunol. 2008 May 1;180(9):5771-7. - id: RGD:6478708 citation: Mege JL, etal., Lancet Infect Dis. 2006 Sep;6(9):557-69. - id: RGD:6478709 citation: Cope A, etal., Trends Immunol. 2011 Jun;32(6):278-86. Epub 2011 Apr 30. - id: RGD:6478710 citation: Rutz S and Ouyang W, Curr Opin Immunol. 2011 Oct;23(5):605-12. Epub 2011 Aug 20. - id: RGD:6478711 citation: Mosser DM and Zhang X, Immunol Rev. 2008 Dec;226:205-18. - id: RGD:6478712 citation: Yoon SI, etal., J Biol Chem. 2006 Nov 17;281(46):35088-96. Epub 2006 Sep 18. - id: RGD:6478713 citation: Commins SP, etal., J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S53-72. Epub 2009 Nov 24. - id: RGD:6480073 citation: Saraiva M and O'Garra A, Nat Rev Immunol. 2010 Mar;10(3):170-81. Epub 2010 Feb 15. - id: RGD:6480074 citation: 'Duell BL, etal., FEMS Immunol Med Microbiol. 2012 Apr;64(3):295-313. doi: 10.1111/j.1574-695X.2012.00931.x. Epub 2012 Feb 14.' - id: RGD:6480251 citation: Cyktor JC and Turner J, Infect Immun. 2011 Aug;79(8):2964-73. Epub 2011 May 16. - id: RGD:6480252 citation: Lee MS and Kim YJ, Annu Rev Biochem. 2007;76:447-80.