IL-4-Stat6 Signaling Induces Tristetraprolin Expression and Inhibits TNF-α Production in Mast Cells

Abstract

Increasing evidence has revealed that mast cell-derived tumor necrosis factor α (TNF-α) plays a critical role in a number of inflammatory responses by recruiting inflammatory leukocytes. In this paper, we investigated the regulatory role of interleukin 4 (IL-4) in TNF-α production in mast cells. IL-4 inhibited immunoglobulin E-induced TNF-α production and neutrophil recruitment in the peritoneal cavity in wild-type mice but not in signal transducers and activators of transcription 6 (Stat6)-deficient mice. IL-4 also inhibited TNF-α production in cultured mast cells by a Stat6-dependent mechanism. IL-4-Stat6 signaling induced TNF-α mRNA destabilization in an AU-rich element (ARE)-dependent manner, but did not affect TNF-α promoter activity. Furthermore, IL-4 induced the expression of tristetraprolin (TTP), an RNA-binding protein that promotes decay of ARE-containing mRNA, in mast cells by a Stat6-dependent mechanism, and the depletion of TTP expression by RNA interference prevented IL-4-induced down-regulation of TNF-α production in mast cells. These results suggest that IL-4-Stat6 signaling induces TTP expression and, thus, destabilizes TNF-α mRNA in an ARE-dependent manner.