AKT(PKB), STAT5, IRS-2, PtdIns(3,4,5)P3, IL-10, Bcl-XL, PtdIns(4,5)P2, PDK (PDPK1), STAT3, IL10RB, p70 S6 kinase1, TIMP1, CRP2, CD14, Bcl-2, p19, 18.104.22.168, TNF-alpha, PI3K reg class IA, STAT1, IL-10 receptor, IL10RA, Tyk2, JAK1, SOCS3, PI3K cat class IA
IL-10 signaling pathway
Interleukin-10 ( IL-10 ) is a pleiotropic cytokine with important immunoregulatory functions. Its actions influence activities of many of the cell-types in the immune system. It is also a cytokine with potent anti-inflammatory properties: it represses the expression of inflammatory cytokines, such as Tumor necrosis factor-alpha ( TNF-alpha ), Interleukin-6 (IL-6) and Interleukin-1 (IL-1 beta), in macrophages , .
Binding of IL-10 to the extracellular domain of IL-10 receptor activates phosphorylation of the receptor-associated Janus kinase 1 ( JAK1 ) and Tyrosine kinase 2 ( Tyk2 ). These kinases then phosphorylate specific tyrosine residues on the intracellular domain of the IL-10 receptor. Once phosphorylated, these tyrosine residues serve as temporary docking sites for the latent transcription factor, Signal transducer and activator of transcription 3 ( STAT3 ). STAT3 binds to these docking sites and is tyrosine-phosphorylated by the receptor-associated JAK1 and Tyk2. STAT3 then homodimerizes and translocates to the nucleus where 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 cell cycle progression, such as Cyclin-dependent kinase inhibitor 2D ( p19 ) , , , , , , , , , , .
IL-10 -induced STAT3 activation results in decreased expression of the inflammatory 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 many inflammatory cytokines, including TNF-alpha, IL-6 and IL-1 beta , , , .
Interaction of IL-10 with IL-10 receptor also results in subsequent tyrosine-phosphorylation of STAT1 and, in non-macrophage cells, STAT5 , , , , . In myeloid cells, IL-10 predominantly activates STAT3 and activated STAT3 is primarily involved in the negative regulation of macrophage activation . The role of STAT1 and STAT5 in IL-10 signal transduction remains unclear, although IL-10-induced CD14 up-regulation in monocytes 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 CRP2 into the nucleus where it up-regulates expression of the TIMP metallopeptidase inhibitor 1 ( TIMP-1 ). TIMP-1 expression in human prostate cancer cells can play a key role in inhibiting tumor growth, perhaps by blocking tumor vascularization , .
IL-10 also activates another major survival pathway consisting of Insulin receptor substrate 2 ( IRS-2 ), Phosphoinositide-3 kinase class IA ( PI3K reg class IA/ PI3K cat class IA ) and its downstream effectors 3-Phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) ), Ribosomal protein S6 kinase 70kDa polypeptide 1 ( p70S6K ) and v-Akt murine thymoma viral oncogene homolog ( AKT(PKB) ) , , .