Immune response IL-10 signaling pathway
IL-10 signaling pathway Interleukin-10 ( IL-10 ) is a pleiotropic cytokine with importantimmunoregulatory functions. Its actions influence activities of many of the cell-types inthe immune system. It is also a cytokine with potent anti-inflammatory properties:it represses the expression of inflammatory cytokines, such as Tumor necrosisfactor-alpha ( TNF-alpha ), Interleukin-6 (IL-6) and Interleukin-1 (IL-1 beta), inmacrophages , . Functional IL-10 receptor complex is a tetramer consisting of two identicalligand-binding subunits ( IL10RA ) and two identical accessory signaling subunits( IL10RB ) , , . Binding of IL-10 to the extracellular domain of IL-10 receptor activatesphosphorylation of the receptor-associated Janus kinase 1 ( JAK1 ) and Tyrosinekinase 2 ( Tyk2 ). These kinases then phosphorylate specific tyrosine residues onthe intracellular domain of the IL-10 receptor. Once phosphorylated, thesetyrosine residues serve as temporary docking sites for the latent transcription factor,Signal transducer and activator of transcription 3 ( STAT3 ). STAT3 bindsto these docking sites and is tyrosine-phosphorylated by the receptor-associatedJAK1 and Tyk2. STAT3 then homodimerizes and translocates to the nucleuswhere it binds to the promoters of various IL-10-responsive genes , , . STAT3 regulates transcription of proapoptotic genes, such as BCL2-like 1 (Bcl-XL ) and B-cell CLL/lymphoma 2 ( Bcl-2 ), and genes inhibiting cellcycle progression, such as Cyclin-dependent kinase inhibitor 2D ( p19 ) , , , , , , , , , , . IL-10 -induced STAT3 activation results in decreased expression of theinflammatory cytokines, such as TNF-alpha . STAT3 also promotes transcription of Suppressor of cytokine signaling 3 (SOCS3 ). SOCS3 acts as a negative feedback regulator of IL-10/JAK1/ STAT3 signaling and inhibits endotoxin-inducible expression of manyinflammatory cytokines, including TNF-alpha, IL-6 and IL-1 beta ,, , . Interaction of IL-10 with IL-10 receptor also results in subsequenttyrosine-phosphorylation of STAT1 and, in non-macrophage cells, STAT5, , , , . Inmyeloid cells, IL-10 predominantly activates STAT3 and activatedSTAT3 is primarily involved in the negative regulation of macrophage activation. The role of STAT1 and STAT5 in IL-10 signaltransduction remains unclear, although IL-10-induced CD14 up-regulation inmonocytes is believed to be mediated by STAT1 , . IL-10 also stimulates tyrosine phosphorylation of Cysteine and glycine-rich protein 2( CRP2 ), probably by JAK1, followed by rapid translocation of CRP2into the nucleus where it up-regulates expression of the TIMP metallopeptidase inhibitor1 ( TIMP-1 ). TIMP-1 expression in human prostate cancer cells can play akey role in inhibiting tumor growth, perhaps by blocking tumor vascularization , . IL-10 also activates another major survival pathway consisting of Insulinreceptor substrate 2 ( IRS-2 ), Phosphoinositide-3 kinase class IA ( PI3K regclass IA/ PI3K cat class IA ) and its downstream effectors 3-Phosphoinositidedependent protein kinase-1 ( PDK (PDPK1) ), Ribosomal protein S6 kinase 70kDapolypeptide 1 ( p70S6K ) and v-Akt murine thymoma viral oncogene homolog (AKT(PKB) ) , , .