Interleukin-10 signaling (Homo sapiens)

From WikiPathways

Jump to: navigation, search
34406, 10, 11, 14, 17...3218, 314, 13, 253321, 23, 24, 29, 41...1, 7, 21, 22, 24...2355, 11, 15, 17, 20...3, 389, 13, 25, 272, 816, 39cytosolnucleoplasmendoplasmic reticulum lumenIL1R2 IL8 gene p-Y496-IL10RA FCER2 gene CCL5(24-91) FCER2(1-321) IL12A gene IL10dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2p-Y-JAK1 CSF1 gene CCL19 CCL3 gene IL10dimer:2xIL10RA:JAK1ATPIL10RB TNFRSF1A gene CCL3L1 gene p-Y705-STAT3 PTAFR gene ADPCXCL1(35-107) CD80 IL10-downregulatedextracellularproteinsADPIL1B IL10RB IL10-downregulatedplasma membraneproteinsCD80 gene IL10 dimerIL10-downregulatedgenes forextracellularproteinsp-Y496-IL10RA IL12B IL1R2 gene LIF gene CCR1 CCL4(24-92) CCL2 CSF1 p-Y496-IL10RA TIMP1 CCL4 gene p-Y446-IL10RA CCR2 TNFRSF1A(41-201),TIMP1CD86 TIMP1 gene CCR5 gene IL10 IL10RA:JAK1IL18 gene IL12B gene CCL22(25-93) ICAM1 gene p-Y-JAK1 FPR1 p-Y705-STAT3 FPR1 gene IL1RN gene PTGS2 geneIL18 JAK1 IL1RN JAK1 p-Y705-STAT3 p-Y-TYK2 IL1R1 gene IL10RA IL10 Myr82K-Myr83K-IL1A IL10 CCL3L1(26-93) ADPATPIL10dimer:2xIL10RA:JAK1:2xIL10RB:TYK2IL6 IL10dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3p-Y705-STAT3 dimerIL10 p-Y-TYK2 CD86 gene IL10 ATPIL1B gene IL1R1 IL10-upregulatedgenes for plasmamembrane proteinsCCR1 gene TNF gene IL12A IL6 gene IL10RA LIF JAK1 p-Y705-STAT3 dimerTYK2 CXCL10(22-98) IL10-downregulatedplasmamembrane-associatedgenesSTAT3p-Y-TYK2 STAT3 TYK2 TNF(77-233) CCL5 gene CSF2 gene PTAFR CSF2 CCR2 gene IL10dimer:2xIL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2CCL20(27-96) CCR5 IL10RA IL10CSF3 gene p-Y446-IL10RA TNFRSF1B(27-?) IL10RB CCL20 gene IL10RB:TYK2CXCL1 gene CCL3(27-92) p-Y-JAK1 IL10 p-Y705-STAT3IL10dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:STAT3IL1A gene p-Y-JAK1 IL10RB IL10 ICAM1 IL10RB p-Y446-IL10RA CXCL2 gene CCL22 gene CXCL2(35-107) CSF3 IL10RB IL10-upregulatedplasma membraneproteinsTNFRSF1B gene IL8 IL10RA p-Y-TYK2 TNFRSF1A gene, TIMP1geneTNFRSF1A(41-201) CCL2 gene CCL19 gene PTGS2CXCL10 gene 12


Description

Interleukin-10 (IL10) was originally described as a factor named cytokine synthesis inhibitory factor that inhibited T-helper (Th) 1 activation and Th1 cytokine production (Fiorentino et al. 1989). It was found to be expressed by a variety of cell types including macrophages, dendritic cell subsets, B cells, several T-cell subpopulations including Th2 and T-regulatory cells (Tregs) and Natural Killer (NK) cells (Moore et al. 2001). It is now recognized that the biological effects of IL10 are directed at antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs), its effects on T-cell development and differentiation are largely indirect via inhibition of macrophage/dendritic cell activation and maturation (Pestka et al. 2004, Mocellin et al. 2004). T cells are thought to be the main source of IL10 (Hedrich & Bream 2010). IL10 inhibits a broad spectrum of activated macrophage/monocyte functions including monokine synthesis, NO production, and expression of class II MHC and costimulatory molecules such as IL12 and CD80/CD86 (de Waal Malefyt et al. 1991, Gazzinelli et al. 1992). Studies with recombinant cytokine and neutralizing antibodies revealed pleiotropic activities of IL10 on B, T, and mast cells (de Waal Malefyt et al. 1993, Rousset et al. 1992, Thompson-Snipes et al. 1991) and provided evidence for the in vivo significance of IL10 activities (Ishida et al. 1992, 1993). IL10 antagonizes the expression of MHC class II and the co-stimulatory molecules CD80/CD86 as well as the pro-inflammatory cytokines IL1Beta, IL6, IL8, TNFalpha and especially IL12 (Fiorentino et al. 1991, D'Andrea et al. 1993). The biological role of IL10 is not limited to inactivation of APCs, it also enhances B cell, granulocyte, mast cell, and keratinocyte growth/differentiation, as well as NK-cell and CD8+ cytotoxic T-cell activation (Moore et al. 2001, Hedrich & Bream 2010). IL10 also enhances NK-cell proliferation and/or production of IFN-gamma (Cai et al. 1999).

IL10-deficient mice exhibited inflammatory bowel disease (IBD) and other exaggerated inflammatory responses (Kuhn et al. 1993, Berg et al. 1995) indicating a critical role for IL10 in limiting inflammatory responses. Dysregulation of IL10 is linked with susceptibility to numerous infectious and autoimmune diseases in humans and mouse models (Hedrich & Bream 2010).

IL10 signaling is initiated by binding of homodimeric IL10 to the extracellular domains of two adjoining IL10RA molecules. This tetramer then binds two IL10RB chains. IL10RB cannot bind to IL10 unless bound to IL10RA (Ding et al. 2001, Yoon et al. 2006); binding of IL10 to IL10RA without the co-presence of IL10RB fails to initiate signal transduction (Kotenko et al. 1997).

IL10 binding activates the receptor-associated Janus tyrosine kinases, JAK1 and TYK2, which are constitutively bound to IL10R1 and IL10R2 respectively. In the classic model of receptor activation assembly of the receptor complex is believed to enable JAK1/TYK2 to phosphorylate and activate each other. Alternatively the binding of IL10 may cause conformational changes that allow the pseudokinase inhibitory domain of one JAK kinase to move away from the kinase domain of the other JAK within the receptor dimer-JAK complex, allowing the two kinase domains to interact and trans-activate (Waters & Brooks 2015).

The activated JAK kinases phosphorylate the intracellular domains of the IL10R1 chains on specific tyrosine residues. These phosphorylated tyrosine residues and their flanking peptide sequences serve as temporary docking sites for the latent, cytosolic, transcription factor, STAT3. STAT3 transiently docks on the IL10R1 chain via its SH2 domain, and is in turn tyrosine phosphorylated by the receptor-associated JAKs. Once activated, it dissociates from the receptor, dimerizes with other STAT3 molecules, and translocates to the nucleus where it binds with high affinity to STAT-binding elements (SBEs) in the promoters of IL-10-inducible genes (Donnelly et al. 1999). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 6783783
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jupe, Steve

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Sozzani S, Ghezzi S, Iannolo G, Luini W, Borsatti A, Polentarutti N, Sica A, Locati M, Mackay C, Wells TN, Biswas P, Vicenzi E, Poli G, Mantovani A.; ''Interleukin 10 increases CCR5 expression and HIV infection in human monocytes.''; PubMed Europe PMC
  2. Finbloom DS, Winestock KD.; ''IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes.''; PubMed Europe PMC
  3. Carpenter RL, Lo HW.; ''STAT3 Target Genes Relevant to Human Cancers.''; PubMed Europe PMC
  4. Liu L, McBride KM, Reich NC.; ''STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3.''; PubMed Europe PMC
  5. Kubin M, Kamoun M, Trinchieri G.; ''Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells.''; PubMed Europe PMC
  6. Kopydlowski KM, Salkowski CA, Cody MJ, van Rooijen N, Major J, Hamilton TA, Vogel SN.; ''Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo.''; PubMed Europe PMC
  7. Calzada-Wack JC, Frankenberger M, Ziegler-Heitbrock HW.; ''Interleukin-10 drives human monocytes to CD16 positive macrophages.''; PubMed Europe PMC
  8. Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD.; ''Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain.''; PubMed Europe PMC
  9. Braunstein J, Brutsaert S, Olson R, Schindler C.; ''STATs dimerize in the absence of phosphorylation.''; PubMed Europe PMC
  10. Dickensheets HL, Donnelly RP.; ''IFN-gamma and IL-10 inhibit induction of IL-1 receptor type I and type II gene expression by IL-4 and IL-13 in human monocytes.''; PubMed Europe PMC
  11. de Waal Malefyt R, Figdor CG, Huijbens R, Mohan-Peterson S, Bennett B, Culpepper J, Dang W, Zurawski G, de Vries JE.; ''Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10.''; PubMed Europe PMC
  12. Walter MR.; ''The molecular basis of IL-10 function: from receptor structure to the onset of signaling.''; PubMed Europe PMC
  13. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T.; ''Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.''; PubMed Europe PMC
  14. Berkman N, John M, Roesems G, Jose PJ, Barnes PJ, Chung KF.; ''Inhibition of macrophage inflammatory protein-1 alpha expression by IL-10. Differential sensitivities in human blood monocytes and alveolar macrophages.''; PubMed Europe PMC
  15. Morinobu A, Kumagai S, Yanagida H, Ota H, Ishida H, Matsui M, Yodoi J, Nakao K.; ''IL-10 suppresses cell surface CD23/Fc epsilon RII expression, not by enhancing soluble CD23 release, but by reducing CD23 mRNA expression in human monocytes.''; PubMed Europe PMC
  16. Zdanov A, Schalk-Hihi C, Wlodawer A.; ''Crystal structure of human interleukin-10 at 1.6 A resolution and a model of a complex with its soluble receptor.''; PubMed Europe PMC
  17. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A.; ''IL-10 inhibits cytokine production by activated macrophages.''; PubMed Europe PMC
  18. Yoon SI, Logsdon NJ, Sheikh F, Donnelly RP, Walter MR.; ''Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex.''; PubMed Europe PMC
  19. Gruber MF, Williams CC, Gerrard TL.; ''Macrophage-colony-stimulating factor expression by anti-CD45 stimulated human monocytes is transcriptionally up-regulated by IL-1 beta and inhibited by IL-4 and IL-10.''; PubMed Europe PMC
  20. D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G.; ''Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells.''; PubMed Europe PMC
  21. Linderholm M, Ahlm C, Settergren B, Waage A, Tärnvik A.; ''Elevated plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, and IL-10 in patients with hemorrhagic fever with renal syndrome.''; PubMed Europe PMC
  22. de Waal Malefyt R, Yssel H, de Vries JE.; ''Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation.''; PubMed Europe PMC
  23. Cassatella MA, Meda L, Gasperini S, Calzetti F, Bonora S.; ''Interleukin 10 (IL-10) upregulates IL-1 receptor antagonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation.''; PubMed Europe PMC
  24. Stearns ME, Rhim J, Wang M.; ''Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/MMP-9 secretion.''; PubMed Europe PMC
  25. Lagos-Quintana M, Rauhut R, Meyer J, Borkhardt A, Tuschl T.; ''New microRNAs from mouse and human.''; PubMed Europe PMC
  26. Willems F, Marchant A, Delville JP, Gérard C, Delvaux A, Velu T, de Boer M, Goldman M.; ''Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes.''; PubMed Europe PMC
  27. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE.; ''Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions.''; PubMed Europe PMC
  28. Jenkins JK, Malyak M, Arend WP.; ''The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils.''; PubMed Europe PMC
  29. te Velde AA, de Waal Malefijt R, Huijbens RJ, de Vries JE, Figdor CG.; ''IL-10 stimulates monocyte Fc gamma R surface expression and cytotoxic activity. Distinct regulation of antibody-dependent cellular cytotoxicity by IFN-gamma, IL-4, and IL-10.''; PubMed Europe PMC
  30. Ding L, Linsley PS, Huang LY, Germain RN, Shevach EM.; ''IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression.''; PubMed Europe PMC
  31. Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S.; ''Identification and functional characterization of a second chain of the interleukin-10 receptor complex.''; PubMed Europe PMC
  32. Donnelly RP, Dickensheets H, Finbloom DS.; ''The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes.''; PubMed Europe PMC
  33. Lai CF, Ripperger J, Morella KK, Jurlander J, Hawley TS, Carson WE, Kordula T, Caligiuri MA, Hawley RG, Fey GH, Baumann H.; ''Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements.''; PubMed Europe PMC
  34. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A.; ''Interleukin-10 and the interleukin-10 receptor.''; PubMed Europe PMC
  35. Niemand C, Nimmesgern A, Haan S, Fischer P, Schaper F, Rossaint R, Heinrich PC, Müller-Newen G.; ''Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3.''; PubMed Europe PMC
  36. Rossi DL, Vicari AP, Franz-Bacon K, McClanahan TK, Zlotnik A.; ''Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta.''; PubMed Europe PMC
  37. Thivierge M, Parent JL, Stankova J, Rola-Pleszczynski M.; ''Modulation of formyl peptide receptor expression by IL-10 in human monocytes and neutrophils.''; PubMed Europe PMC
  38. Lo HW, Cao X, Zhu H, Ali-Osman F.; ''Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes.''; PubMed Europe PMC
  39. Syto R, Murgolo NJ, Braswell EH, Mui P, Huang E, Windsor WT.; ''Structural and biological stability of the human interleukin 10 homodimer.''; PubMed Europe PMC
  40. Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW.; ''Expression cloning and characterization of a human IL-10 receptor.''; PubMed Europe PMC
  41. Lacraz S, Nicod LP, Chicheportiche R, Welgus HG, Dayer JM.; ''IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes.''; PubMed Europe PMC
  42. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE.; ''Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.''; PubMed Europe PMC
  43. Mertz PM, DeWitt DL, Stetler-Stevenson WG, Wahl LM.; ''Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production.''; PubMed Europe PMC
  44. Hart PH, Hunt EK, Bonder CS, Watson CJ, Finlay-Jones JJ.; ''Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10.''; PubMed Europe PMC
  45. Dickensheets HL, Freeman SL, Smith MF, Donnelly RP.; ''Interleukin-10 upregulates tumor necrosis factor receptor type-II (p75) gene expression in endotoxin-stimulated human monocytes.''; PubMed Europe PMC
  46. Marfaing-Koka A, Maravic M, Humbert M, Galanaud P, Emilie D.; ''Contrasting effects of IL-4, IL-10 and corticosteroids on RANTES production by human monocytes.''; PubMed Europe PMC
  47. Andrew DP, Chang MS, McNinch J, Wathen ST, Rihanek M, Tseng J, Spellberg JP, Elias CG.; ''STCP-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13.''; PubMed Europe PMC
  48. Joyce DA, Steer JH.; ''IL-4, IL-10 and IFN-gamma have distinct, but interacting, effects on differentiation-induced changes in TNF-alpha and TNF receptor release by cultured human monocytes.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
101650view11:51, 1 November 2018ReactomeTeamreactome version 66
101186view21:39, 31 October 2018ReactomeTeamreactome version 65
100713view20:11, 31 October 2018ReactomeTeamreactome version 64
100263view16:57, 31 October 2018ReactomeTeamreactome version 63
99816view15:21, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93367view11:21, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CCL19 ProteinQ99731 (Uniprot-TrEMBL)
CCL19 gene ProteinENSG00000172724 (Ensembl)
CCL2 ProteinP13500 (Uniprot-TrEMBL)
CCL2 gene ProteinENSG00000108691 (Ensembl)
CCL20 gene ProteinENSG00000115009 (Ensembl)
CCL20(27-96) ProteinP78556 (Uniprot-TrEMBL)
CCL22 gene ProteinENSG00000102962 (Ensembl)
CCL22(25-93) ProteinO00626 (Uniprot-TrEMBL)
CCL3 gene ProteinENSG00000277632 (Ensembl)
CCL3(27-92) ProteinP10147 (Uniprot-TrEMBL)
CCL3L1 gene ProteinENSG00000277768 (Ensembl)
CCL3L1(26-93) ProteinP16619 (Uniprot-TrEMBL)
CCL4 gene ProteinENSG00000275302 (Ensembl)
CCL4(24-92) ProteinP13236 (Uniprot-TrEMBL)
CCL5 gene ProteinENSG00000271503 (Ensembl)
CCL5(24-91) ProteinP13501 (Uniprot-TrEMBL)
CCR1 ProteinP32246 (Uniprot-TrEMBL)
CCR1 gene ProteinENSG00000163823 (Ensembl)
CCR2 ProteinP41597 (Uniprot-TrEMBL)
CCR2 gene ProteinENSG00000121807 (Ensembl)
CCR5 ProteinP51681 (Uniprot-TrEMBL)
CCR5 gene ProteinENSG00000160791 (Ensembl)
CD80 ProteinP33681 (Uniprot-TrEMBL)
CD80 gene ProteinENSG00000121594 (Ensembl)
CD86 ProteinP42081 (Uniprot-TrEMBL)
CD86 gene ProteinENSG00000114013 (Ensembl)
CSF1 ProteinP09603 (Uniprot-TrEMBL)
CSF1 gene ProteinENSG00000184371 (Ensembl)
CSF2 ProteinP04141 (Uniprot-TrEMBL)
CSF2 gene ProteinENSG00000164400 (Ensembl)
CSF3 ProteinP09919 (Uniprot-TrEMBL)
CSF3 gene ProteinENSG00000108342 (Ensembl)
CXCL1 gene ProteinENSG00000163739 (Ensembl)
CXCL1(35-107) ProteinP09341 (Uniprot-TrEMBL)
CXCL10 gene ProteinENSG00000169245 (Ensembl)
CXCL10(22-98) ProteinP02778 (Uniprot-TrEMBL)
CXCL2 gene ProteinENSG00000081041 (Ensembl)
CXCL2(35-107) ProteinP19875 (Uniprot-TrEMBL)
FCER2 gene ProteinENSG00000104921 (Ensembl)
FCER2(1-321) ProteinP06734 (Uniprot-TrEMBL)
FPR1 ProteinP21462 (Uniprot-TrEMBL)
FPR1 gene ProteinENSG00000171051 (Ensembl)
ICAM1 ProteinP05362 (Uniprot-TrEMBL)
ICAM1 gene ProteinENSG00000090339 (Ensembl)
IL10 dimer:2xIL10RA:JAK1:2xIL10RB:TYK2ComplexR-HSA-449832 (Reactome)
IL10 dimer:2xIL10RA:JAK1ComplexR-HSA-449802 (Reactome)
IL10 dimer:2xIL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2ComplexR-HSA-6784339 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:STAT3ComplexR-HSA-6784795 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3ComplexR-HSA-6784779 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2ComplexR-HSA-6784755 (Reactome)
IL10 ProteinP22301 (Uniprot-TrEMBL)
IL10 dimerComplexR-HSA-449854 (Reactome)
IL10-downregulated

extracellular

proteins
ComplexR-HSA-6784987 (Reactome)
IL10-downregulated

genes for extracellular

proteins
ComplexR-HSA-6784990 (Reactome)
IL10-downregulated

plasma membrane-associated

genes
ComplexR-HSA-8937649 (Reactome)
IL10-downregulated

plasma membrane

proteins
ComplexR-HSA-8937653 (Reactome)
IL10-upregulated

genes for plasma

membrane proteins
ComplexR-HSA-8937655 (Reactome)
IL10-upregulated

plasma membrane

proteins
ComplexR-HSA-8937648 (Reactome)
IL10ProteinP22301 (Uniprot-TrEMBL)
IL10RA ProteinQ13651 (Uniprot-TrEMBL)
IL10RA:JAK1ComplexR-HSA-6783816 (Reactome)
IL10RB ProteinQ08334 (Uniprot-TrEMBL)
IL10RB:TYK2ComplexR-HSA-6784360 (Reactome)
IL12A ProteinP29459 (Uniprot-TrEMBL)
IL12A gene ProteinENSG00000168811 (Ensembl)
IL12B ProteinP29460 (Uniprot-TrEMBL)
IL12B gene ProteinENSG00000113302 (Ensembl)
IL18 ProteinQ14116 (Uniprot-TrEMBL)
IL18 gene ProteinENSG00000150782 (Ensembl)
IL1A gene ProteinENSG00000115008 (Ensembl)
IL1B ProteinP01584 (Uniprot-TrEMBL)
IL1B gene ProteinENSG00000125538 (Ensembl)
IL1R1 ProteinP14778 (Uniprot-TrEMBL)
IL1R1 gene ProteinENSG00000115594 (Ensembl)
IL1R2 ProteinP27930 (Uniprot-TrEMBL)
IL1R2 gene ProteinENSG00000115590 (Ensembl)
IL1RN ProteinP18510 (Uniprot-TrEMBL)
IL1RN gene ProteinENSG00000136689 (Ensembl)
IL6 ProteinP05231 (Uniprot-TrEMBL)
IL6 gene ProteinENSG00000136244 (Ensembl)
IL8 ProteinP10145 (Uniprot-TrEMBL)
IL8 gene ProteinENSG00000169429 (Ensembl)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
LIF ProteinP15018 (Uniprot-TrEMBL)
LIF gene ProteinENSG00000128342 (Ensembl)
Myr82K-Myr83K-IL1A ProteinP01583 (Uniprot-TrEMBL)
PTAFR ProteinP25105 (Uniprot-TrEMBL)
PTAFR gene ProteinENSG00000169403 (Ensembl)
PTGS2 geneGeneProductENSG00000073756 (Ensembl)
PTGS2ProteinP35354 (Uniprot-TrEMBL)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT3ProteinP40763 (Uniprot-TrEMBL)
TIMP1 ProteinP01033 (Uniprot-TrEMBL)
TIMP1 gene ProteinENSG00000102265 (Ensembl)
TNF gene ProteinENSG00000232810 (Ensembl)
TNF(77-233) ProteinP01375 (Uniprot-TrEMBL)
TNFRSF1A gene ProteinENSG00000067182 (Ensembl)
TNFRSF1A gene, TIMP1 geneComplexR-HSA-6785052 (Reactome)
TNFRSF1A(41-201) ProteinP19438 (Uniprot-TrEMBL)
TNFRSF1A(41-201),TIMP1ComplexR-HSA-6785069 (Reactome)
TNFRSF1B gene ProteinENSG00000028137 (Ensembl)
TNFRSF1B(27-?) ProteinP20333 (Uniprot-TrEMBL)
TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y-TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y446-IL10RA ProteinQ13651 (Uniprot-TrEMBL)
p-Y496-IL10RA ProteinQ13651 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3 dimerComplexR-HSA-1112525 (Reactome)
p-Y705-STAT3 dimerComplexR-HSA-1112526 (Reactome)
p-Y705-STAT3ProteinP40763 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6784006 (Reactome)
ADPArrowR-HSA-6784319 (Reactome)
ADPArrowR-HSA-6784324 (Reactome)
ATPR-HSA-6784006 (Reactome)
ATPR-HSA-6784319 (Reactome)
ATPR-HSA-6784324 (Reactome)
IL10 dimer:2xIL10RA:JAK1:2xIL10RB:TYK2ArrowR-HSA-449811 (Reactome)
IL10 dimer:2xIL10RA:JAK1:2xIL10RB:TYK2R-HSA-6784319 (Reactome)
IL10 dimer:2xIL10RA:JAK1:2xIL10RB:TYK2mim-catalysisR-HSA-6784319 (Reactome)
IL10 dimer:2xIL10RA:JAK1ArrowR-HSA-449803 (Reactome)
IL10 dimer:2xIL10RA:JAK1R-HSA-449811 (Reactome)
IL10 dimer:2xIL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2ArrowR-HSA-6784319 (Reactome)
IL10 dimer:2xIL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2R-HSA-6784324 (Reactome)
IL10 dimer:2xIL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2mim-catalysisR-HSA-6784324 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:STAT3ArrowR-HSA-6784323 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:STAT3R-HSA-6784006 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:STAT3mim-catalysisR-HSA-6784006 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3ArrowR-HSA-6784006 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3R-HSA-6784791 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2ArrowR-HSA-6784324 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2ArrowR-HSA-6784791 (Reactome)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2R-HSA-6784323 (Reactome)
IL10 dimerArrowR-HSA-449855 (Reactome)
IL10 dimerR-HSA-449803 (Reactome)
IL10-downregulated

extracellular

proteins
ArrowR-HSA-6784160 (Reactome)
IL10-downregulated

genes for extracellular

proteins
R-HSA-6784160 (Reactome)
IL10-downregulated

plasma membrane-associated

genes
R-HSA-8937656 (Reactome)
IL10-downregulated

plasma membrane

proteins
ArrowR-HSA-8937656 (Reactome)
IL10-upregulated

genes for plasma

membrane proteins
R-HSA-8937654 (Reactome)
IL10-upregulated

plasma membrane

proteins
ArrowR-HSA-8937654 (Reactome)
IL10ArrowR-HSA-6785047 (Reactome)
IL10ArrowR-HSA-8937654 (Reactome)
IL10R-HSA-449855 (Reactome)
IL10RA:JAK1R-HSA-449803 (Reactome)
IL10RB:TYK2R-HSA-449811 (Reactome)
IL10TBarR-HSA-6784160 (Reactome)
IL10TBarR-HSA-8937656 (Reactome)
PTGS2 geneR-HSA-6790029 (Reactome)
PTGS2ArrowR-HSA-6790029 (Reactome)
R-HSA-449803 (Reactome) The IL-10 receptor is composed of at least two subunits, both members of the interferon receptor (IFNR) family (Liu et al. 1994). Interferon-10 receptor alpha chain (IL10RA) is the ligand-binding subunit, binding IL-10 with high affinity (Kd 35-200 pM) (Tan et al. 1993). IL10RA is constitutively associated with JAK1 (Moore et al. 2001, Usacheva et al. 2002). This association is dependent on a membrane-proximal part of the receptor (amino acids 269-274) which contain a region designated the box 2B motif, characterized by a core of four hydrophobic residues flanked by a serine and charged residues (Usacheva et al. 2002).
R-HSA-449811 (Reactome) Interleukin-10 receptor chain B (IL10RB, IL10R2, CRF2-4) binds the IL1-10:IL10RA complex, causing conformational changes that allow it to bind IL-10 (Yoon et al. 2010). IL10RB is essential for signal transduction (Kotenko et al. 1997). It is constitutively bound to the JAK family kinase TYK2 (Kotenko et al. 1997, Spencer et al. 1998).

IL10RB can also combine with either IL-22R1, IFN-lambdaR1 or IL-20R1 to assemble the IL-22, IFN-lambda or IL-26 receptor complexes, respectively (Kotenko & Langer 2004).
R-HSA-449855 (Reactome) Interleukin-10 is predominantly a noncovalent homodimer with structural similarities to interferon-gamma.
R-HSA-6784006 (Reactome) STAT3 bound to IL10RA is tyrosine phosphorylated by the receptor-associated JAKs (Niemand et al. 2003, Liu et al. 2005).
R-HSA-6784160 (Reactome) IL10 modulates the expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses. The effects of IL10 on cytokine production and function of human macrophages are generally similar to those on monocytes, although less pronounced (Moore et al. 2001). IL10 inhibits production of Interleukin-1 alpha (IL1A), IL1B, IL6, IL12, IL18, CSF2 (GM-CSF), CSF3 (G-CSF), CSF1 (M-CSF), TNF, LIF, PAF and itself by activated monocytes/macrophages (de Waal Malefyt et al. 1991, 1993, Fiorentino et al. 1991, D'Andrea et al. 1993, Gruber et al. 1994). The effect of IL10 on IL-1 and TNF production is particularly important as these cytokines often have synergistic effects on inflammatory processes, amplifying their effect by inducing secondary mediators such as chemokines, prostaglandins and PAF. IL10 also inhibits activated monocyte production of inducible chemokines that are involved in inflammation, namely CCL2 (MCP1), Ccl12 (MCP-5, in mice), CCL3, CCL3L1 (Mip-1alpha), CCL4 (Mip-1beta), CCL20 (Mip-3alpha), CCL19 (Mip-3beta), CCL5 (Rantes), CCL22 (MDC), CXCL8 (IL-8), CXCL10 (IP-10), CXCL2 (MIP-2) and CXCL1 (KC, Gro-alpha) (Berkman et al. 1995, Rossi et al. 1997, Marfaing-Koka et al. 1996, Kopydlowski et al. 1999). These are involved in the recruitment of monocytes, dendritic cells, neutrophils, and T cells, and affect both Th1 and Th2 responses. CXCL1 is induced by IFNgamma and attracts Th1 cells; CCL22 is induced by IL-4 and attracts Th2 cells.

IL10 inhibits expression of IL1R1 and IL-1RII (de Waal Malefyt et al. 1991, Jenkins et al. 1994, Dickensheets & Donnelly 1997).

Both transcriptional and posttranscriptional mechanisms have been implicated in the inhibitory effects of IL10 on cytokine and chemokine production (Bogdan et al. 1991, Clarke et al. 1998, Brown et al. 1996). IL10 regulates production of certain cytokines, such as CXCL1, by destabilizing mRNA via AU-rich elements in the 3'-UTR of sensitive genes (Kim et al. 1998, Kishore et al. 1999). IL-10 also enhances IL-1RA expression via inhibition of mRNA degradation (Cassatella et al. 1994).

IL10 indirectly inhibits production of prostaglandin E2 (PGE2) by downregulating PTGS2 (cyclooxygenase 2) expression (Niiro et al. 1994, 1995, Mertz et al. 1994), which also reduces expression of Matrix metalloproteinase 2 (MMP2) and MMP9, thereby modulating extracellular matrix turnover.
R-HSA-6784319 (Reactome) Binding of IL-10 to its receptor causes phosphorylation and activation of the receptor-associated Janus tyrosine kinases, JAK1 and TYK2 (Finbloom & Winestock 1995), leading to phosphorylation of two conserved tyrosine residues (Y446 and Y496) within the intracellular domain of IL10RA, which serve as redundant docking sites for STAT3 (Ho et al. 1995, Weber-Nordt et al. 1996).

The details of JAK kinase activation are unclear. The classical model suggests that receptor dimerization, induced by ligand binding, brings the two JAK family kinases into proximity, so that they are able to trans-activate (phosphorylate) each other (Donnelly et al. 1999, Waters et al. 2015) but it is also possible that ligand binding causes a conformational change in a pre-existing receptor dimer that withdraws trans pseudo-kinase inhibition for paired kinases, which then autophosphorylate (Waters et al. 2014, Waters & Brooks 2015). JAK1, like all JAK kinases, has two adjacent tyrosines in its activation loop (Y1034, Y1035). It is not known which of these becomes phosphorylated in response to IL10 binding, or if phosphorylation at one site rather than the other has functional consequences. In vitro, phosphorylation at Y1034 has a greater enhancing effect on JAK1 catalytic ability (Wang et al. 2003) and is the more commonly observed phosphorylation site (see PhosphoSitePlus). Similarly TYK2 has two adjacent tyrosines, the first (Y1054) is the more commonly observed (see PhosphoSitePlus).
R-HSA-6784323 (Reactome) STAT3 is recruited directly to the receptor complex via either of the two tyrosine residues in the IL10R1 cytoplasmic domain (Y446 and Y496) that become phosphorylated in response to IL-10 (Weber-Nordt et al. 1996, Riley et al. 1999). Overexpression of a dominant negative mouse Stat3 mutant or an inducibly-active form of mouse Stat3 demonstrated that Stat3 activation is necessary and sufficient to mediate inhibition of macrophage proliferation by IL-10 (O'Farrell et al. 1998) at least in part via enhancement of CDKN2D (INK4d) and CDKN1A (CIP1) expression (O'Farrell et al. 2000). In contrast, the Stat3 mutant did not detectably impair IL-10's ability to inhibit LPS-induced monokine production suggesting that IL10 inhibition of macrophage proliferation and monokine production are the result of two distinct signaling pathways (O'Farrell et al. 1998). Stat3 conditional knockout mice develop chronic enterocholitis and have macrophages that show no response to IL10 (Riley et al. 1999, Takeda et al. 1999).
R-HSA-6784324 (Reactome) Binding of IL-10 leads to activation of the receptor-associated Janus tyrosine kinases, JAK1 and TYK2 (Finbloom & Winestock 1995), leading to phosphorylation of IL10RA at two conserved intracellular tyrosine residues (Y446 and Y496) that serve as docking sites for STAT molecules (Ho et al. 1995, Weber-Nordt et al. 1996).

The details of receptor phosphorylation are unclear. Most descriptions of IL10 receptor tyrosine phosphorylation (Donnelly et al. 1999, Carey et al. 2012) suggest that JAK1 and TYK2 are responsible for IL10RA phosphorylation but it is not clear whether one or both kinases are responsible for phosphorylating IL10RA.
R-HSA-6784763 (Reactome) The classical model of JAK-STAT signaling suggests that phosphorylated Signal transducer and activator of transcription 3 (STAT3) translocates to the nucleus (Akira et al. 1994) where it binds DNA to mediate the effects of Interleukin-10 (IL10) on expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses. STAT3 is able to shuttle freely between the cytoplasm and the nucleus, independent of tyrosine phosphorylation (Liu et al. 2005, Li 2008, Reich 2013). Binding of unphosphorylated STAT3 to DNA has been reported (Nkansah et al. 2013). As it is not clear what triggers nuclear accumulation of STAT3 in response to IL10 this event is shown as an uncertain process.
R-HSA-6784765 (Reactome) Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dimerizes after dissociating from the interleukin-19 (IL19) receptor complex (Akira et al. 1994) or Interleukin-22 (IL22) receptor complex (Lagos-Quintana et al. 2003, Sestito et al. 2011).

According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
R-HSA-6784791 (Reactome) Once phosphorylated, STAT3 dissociates from the receptor, dimerizes with other STAT3 molecules, and translocates to the nucleus where it binds with high affinity to STAT-binding elements (SBEs) in the promoters of IL-10-inducible genes (Donnelly et al. 1999).
R-HSA-6785047 (Reactome) IL10 enhances activated monocyte expression of the natural antagonists interleukin-1 receptor antagonist (IL1RN), TNFRSF1A (soluble p55 TNFR) and TNFRSF1B (p75 TNFR) (Cassatella et al 1994, Hart et al. 1996, Joyce & Steer 1996, Linderholm et al. 1996, Dickensheets et al. 1997).

IL10 enhances production of tissue inhibitor of metalloproteinases (TIMP1) and hyaluronectin, which bind and inhibit the angiogenic- and migration-promoting activities of hyaluronic acid (Mertz et al. 1994, Lacraz et al. 1995, Stearns et al. 1999, Girard et al. 1999).
R-HSA-6790029 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014), including the gene which encodes the endoplasmic reticulum membrane protein Prostaglandin G/H synthase 2 (PTGS2, COX2) (Lo et al. 2010).
R-HSA-8937654 (Reactome) IL10 upregulates monocyte expression of FPR1 (fMLP receptor), PTAFR (PAF receptor), CCR1, CCR2, and CCR5, making them more responsive to chemotactic factors (Andrew et al. 1998, Sozzani et al. 1998, Thivierge et al. 1999) and more susceptible to HIV infection (Andrew et al. 1998, Sozzani et al. 1998).
IL10 enhances activated monocyte expression of the natural antagonists interleukin-1 receptor antagonist (IL1RN) and TNFRSF1B (p75 TNFR) (Cassatella et al 1994, Hart et al. 1996, Joyce & Steer 1996, Linderholm et al. 1996, Dickensheets et al. 1997).

IL10 enhances production of tissue inhibitor of metalloproteinases (TIMP1) and hyaluronectin, which bind and inhibit the angiogenic- and migration-promoting activities of hyaluronic acid (Mertz et al. 1994, Lacraz et al. 1995, Stearns et al. 1999, Girard et al. 1999).

IL10 enhances expression of CD16 and CD64 FcgammaR on monocytes (te Velde et al. 1992, de Waal Malefyt et al. 1993, Calzada-Wack et al. 1996).
R-HSA-8937656 (Reactome) IL10 modulates the expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses. The effects of IL10 on cytokine production and function of human macrophages are generally similar to those on monocytes, although less pronounced (Moore et al. 2001).

IL10 inhibits expression of IL1R1 and IL-1RII (de Waal Malefyt et al. 1991, Jenkins et al. 1994, Dickensheets & Donnelly 1997).

Both transcriptional and posttranscriptional mechanisms have been implicated in the inhibitory effects of IL10 on cytokine and chemokine production (Bogdan et al. 1991, Clarke et al. 1998, Brown et al. 1996).

IL10 inhibits monocyte expression of MHC class II antigens, ICAM1 (CD54), CD80 (B7), CD86 (B7.2) and FCER2 (CD23), countering the induction of these molecules by IL-4 or IFNgamma (de Waal Malefyt et al. 1991, Ding et al. 1993, Kubin et al. 1994, Willems et al. 1994, Morinobu et al. 1996). Downregulated expression of these molecules significantly decreases the T cell-activating capacity of monocyte APCs (de Waal Malefyt et al. 1991, Fiorentino et al. 1991, Ding et al. 1993).
STAT3R-HSA-6784323 (Reactome)
TNFRSF1A gene, TIMP1 geneR-HSA-6785047 (Reactome)
TNFRSF1A(41-201),TIMP1ArrowR-HSA-6785047 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6784763 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6784765 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790029 (Reactome)
p-Y705-STAT3 dimerR-HSA-6784763 (Reactome)
p-Y705-STAT3ArrowR-HSA-6784791 (Reactome)
p-Y705-STAT3R-HSA-6784765 (Reactome)
Personal tools