Interleukin-10 signaling

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 unphos-phorylated 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.


Interleukin-10 signaling ↗ Stable identifier: R-HSA-6783783
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 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(Ishida et al. , 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. Al-ternatively 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).

Literature references
Wlodawer, A., Schalk-Hihi, C., Zdanov, A. (1996). Crystal structure of human interleukin-10 at 1. 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).
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).
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.