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 tetramers consisting of two IL-10R1 polypeptide chains and two IL-10R2 chains. Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation 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, 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 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 family of genes that inhibit JAK/STAT-dependent signaling. Moreover, the ability 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, including 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 monocytes is associated with its ability to rapidly induce synthesis of SOCS-3.
Donnelly
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Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. donnelly@cber.fda.gov
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D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D008070:Lipopolysaccharides; D016753:Interleukin-10; D015847:Interleukin-4; D007372:Interferons