The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes

Interleukin-10 (IL-10) activates a diverse array of functional responses in mononuclear phagocytes, Functional IL-10 receptor (IL-10R) complexes are t etramers consisting of two IL-10R1 polypeptide chains and two IL-10R2 chain s, Binding of IL-10 to the extracellular domain of IL-10R1 activates phosph orylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2, These kinases then phosphorylate specific tyrosine residues (Y446 and Y496 ) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, th ese tyrosine residues (and their flanking peptide sequences) serve as tempo rary docking sites for the latent transcription factor, STAT3 (signal trans ducer and activator of transcription-3). STAT3 binds to these sites via its SH2 (Src homology 2) domain, and is, in turn, tyrosine-phosphorylated by t he receptor-associated JAKs, It then homodimerizes and translocates to the nucleus where it binds with high affinity to STAT-binding elements (SBE) in the promoters of various IL-10-responsive genes, One of these genes, SOCS- 3 (Suppressor of Cytokine Signaling-3) is a member of a newly identified fa mily of genes that inhibit JAK/STAT-dependent signaling. Moreover, the abil ity of IL-10 to induce de novo synthesis of SOCS-3 in monocytes correlates with its ability to inhibit expression of many genes in these cells, includ ing endotoxin-inducible cytokines such as tumor necrosis factor-alpha (TNF- alpha) and IL-1, Thus, the ability of IL-10 to inhibit gene expression in m onocytes is associated with its ability to rapidly induce synthesis of SOCS -3.