Interleukin-10 signaling (Homo sapiens)
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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.
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.
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DataNodes
extracellular
proteinsgenes for extracellular
proteinsplasma membrane-associated
genesplasma membrane
proteinsgenes for plasma
membrane proteinsplasma membrane
proteinsAnnotated Interactions
extracellular
proteinsgenes for extracellular
proteinsplasma membrane-associated
genesplasma membrane
proteinsgenes for plasma
membrane proteinsplasma membrane
proteinsIL10RB 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).
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.
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).
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.
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.
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 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).
IL10 inhibits expression of IL1R1 and IL-1RII (de Waal Malefyt et al. 1991, Jenkins et al. 1994, Dickensheets & Donnelly 1997).
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).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).