The Interleukin-10 Signal Transduction Pathway and Regulation of Gene Expression in Mononuclear Phagocytes

Abstract

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-phosphorylate d 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-a (TNF-a ) 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. 563

Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils

“…4, C and D). The dampening of TNF-␣ production is mediated through numerous, mechanically distinct, mechanisms involving diverse, intracellular signaling pathways (55)(56)(57). The particular mechanism in our model remains to be elucidated.…”

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…IL-10 binds to a receptor tetramer complex that activates phosphorylation of Janus tyrosine kinases, JAK1 and Tyk2, which then phosphorylate two specific tyrosine residues that form part of a docking site for signal transducer and activator of transcription-3 (STAT-3). STAT-3 is tyrosine phosphorylated by the receptor associated JAKs and then translocates to the nucleus where it binds to STAT binding elements in the promoters of various genes (49). Ricchetti and colleagues found that IL-10-induced expression of HO-1 requires STAT-3 in macrophage cell lines.…”

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

“…Because SOSC3 can negatively regulate responses to different activating cytokines and bacterial products, it is speculated that the anti-inflammatory action of IL-10 is due to induction of SOCS3 [42] . Here, however, our analysis of the expression of IL-10/STAT3 signaling shows that the irradiation-induced SOCS3 overexpression was instead associated with suppression of IL-10 mRNA and STAT3 protein.…”