IL-10 (Interleukin-10) is a pleiotropic cytokine with important immunoregulatory functions whose actions influence activities of many of the cell-types in the immune system. It is a cytokine with potent anti-inflammatory properties, repressing the express ...ion of inflammatory cytokines such as TNF-Alpha (Tumor Necrosis Factor-Alpha), IL-6 (Interleukin-6) and IL-1 (Interleukin-1) by activated macrophages. Functional IL-10R (IL-10 Receptor) complexes are tetramers consisting of two ligand-binding subunits (IL-10R-Alpha or IL-10R1) and two accessory signaling subunits (IL-10R-Beta or IL-10R2). Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated, JAK1 (Janus Kinase-1) and TYK2 (Tyrosine Kinase-2), which are constitutively associated with IL-10R1 and IL-10R2, respectively. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (Signal Transducer and Activator of Transcription-3). STAT3 binds to these sites via its SH2 (Src Homology-2) domain, and is, in turn, tyrosine-phosphorylated by the receptor-associated JAKs. It then homodimerizes and translocates to the nucleus where it binds with high affinity to SBE (STAT-Binding Elements) in the promoters of various IL-10-responsive genes. Constitutively active forms of STAT3 increase transcription of anti-apoptotic and cell-cycle-progression genes such as BCLXL, Cyclin-D1, Cyclin-D2, Cyclin-D3, Pim1, c-Myc and p19 (INK4D). IL-10 has also been reported to activate another major survival pathway consisting of PI3K (Phosphoinositide-3 Kinase).Although the anti-inflammatory effects of IL-10 are not mediated via PI3K, the ability of IL-10 to promote survival of astrocytes or to induce proliferation of mast cells depends upon the activation of PI3K. IL-10 also interferes with the activation potential of the p38MAPK (Mitogen-Activated Protein Kinase) pathway, which is required to activate TNF (Tumor Necrosis Factor) translation.
View More... View Less...