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Interleukin-10 signaling
Stable Identifier
R-HSA-6783783
DOI
10.3180/R-HSA-6783783.1
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Immune System (Homo sapiens)
Cytokine Signaling in Immune system (Homo sapiens)
Signaling by Interleukins (Homo sapiens)
Interleukin-10 signaling (Homo sapiens)
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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).
Literature References
PubMed ID
Title
Journal
Year
11244051
Interleukin-10 and the interleukin-10 receptor
Moore, KW
,
O'Garra, A
,
Coffman, RL
,
de Waal Malefyt, R
Annu. Rev. Immunol.
2001
Participants
Events
IL10 dimerizes
(Homo sapiens)
IL10 dimer binds IL10RA:JAK1
(Homo sapiens)
IL10 dimer:2xIL10RA1:JAK1 binds IL10RB:TYK2
(Homo sapiens)
JAK1,TYK2 phosphorylate JAK1,TYK2
(Homo sapiens)
p-Y-JAK1,p-Y-TYK2 phosphorylate IL10RA
(Homo sapiens)
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2 binds STAT3
(Homo sapiens)
STAT3 is phosphorylated by p-Y-JAK1,P-Y-TYK2
(Homo sapiens)
p-Y705-STAT3 dissociates from IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3
(Homo sapiens)
p-Y705-STAT3 dimerizes
(Homo sapiens)
p-Y705-STAT3 dimer translocates from cytosol to nucleoplasm
(Homo sapiens)
IL10 negatively regulates extracellular inflammatory mediators
(Homo sapiens)
IL10 negatively regulates plasma membrane-associated inflammatory mediators
(Homo sapiens)
Expression of PTGS2
(Homo sapiens)
IL10 positively regulates extracellular inflammatory mediators
(Homo sapiens)
IL10 positively regulates plasma membrane-associated inflammatory mediators
(Homo sapiens)
Participates
as an event of
Signaling by Interleukins (Homo sapiens)
Event Information
Go Biological Process
cytokine-mediated signaling pathway (0019221)
Orthologous Events
Interleukin-10 signaling (Bos taurus)
Interleukin-10 signaling (Caenorhabditis elegans)
Interleukin-10 signaling (Canis familiaris)
Interleukin-10 signaling (Danio rerio)
Interleukin-10 signaling (Dictyostelium discoideum)
Interleukin-10 signaling (Drosophila melanogaster)
Interleukin-10 signaling (Gallus gallus)
Interleukin-10 signaling (Mus musculus)
Interleukin-10 signaling (Rattus norvegicus)
Interleukin-10 signaling (Sus scrofa)
Interleukin-10 signaling (Xenopus tropicalis)
Cross References
BioModels Database
BIOMD0000000504
,
BIOMD0000000477
Authored
Jupe, S (2015-06-17)
Reviewed
Meldal, BH (2016-09-05)
Created
Jupe, S (2015-06-17)
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