Opposite functions of STAT3 and Smad3 in regulating Tiam1 expression in Th17 cells

Abstract

We recently showed that Tiam1 expression is induced in pro-inflammatory T helper 17 (Th17) cells differentiated with interleukin (IL)-6 and TGF-β1, and together with Rac1 promote Th17 cell development and autoimmunity in a mouse model of multiple sclerosis. Here we found that STAT3 and Smad3, downstream transcription factors of IL-6 and TGF-β1, respectively, play opposing roles in regulating Tiam1 transcription in CD4+ T-cells. While IL-6-STAT3 signaling promotes Tiam1 expression, TGF-β1-Smad3 induces the opposite outcome. At the Tiam1 promoter, both STAT3 and Smad3 bind to the Tiam1 promoter in Th17 cells. However, STAT3 induces Tiam1 promoter activity whereas Smad3 competes with STAT3 and inhibits its activity. Our findings uncover the complexity of STAT3/Smad3 signaling in regulating Tiam1 expression and Th17 cells.