Immune response - IL-10 signaling pathway

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 [1], [2].

Functional IL-10 receptor complex is a tetramer consisting of two identical ligand-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 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 [1], [6], [7].

STAT3 regulates transcription of anti-apoptotic 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) [5], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

IL-10-induced STAT3 activation results in decreased expression of the inflammatory 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 many inflammatory 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 subsequent tyrosine-phosphorylation of STAT1 and, in non-macrophage cells, STAT5 [6], [22], [23], [24], [25]. In myeloid cells, IL-10 predominantly activates STAT3 and activated STAT3 is primarily involved in the negative regulation of macrophage activation [26]. 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 [1], [27].

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 [28], [29].

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

References:

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