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Immune response IL-10 signaling pathway

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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 [1], [2].

Functional IL-10 receptor complex is a tetramer consisting of two identicalligand-binding subunits ( IL10RA ) and two identical accessory signaling subunits( IL10RB ) [3], [4], [5].

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 [6], [1], [7].

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 ) [5], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

IL-10 -induced STAT3 activation results in decreased expression of theinflammatory cytokines, such as TNF-alpha [2].

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 [18],[19], [20], [21].

Interaction of IL-10 with IL-10 receptor also results in subsequenttyrosine-phosphorylation of STAT1 and, in non-macrophage cells, STAT5[6], [22], [23], [24], [25]. Inmyeloid cells, IL-10 predominantly activates STAT3 and activatedSTAT3 is primarily involved in the negative regulation of macrophage activation[26]. 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 [1], [27].

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 [28], [29].

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) ) [30], [31], [1].