Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3.
EAE; IL17A; IL1R1; RORγt; p300; pathogenic Th17; steroid receptor coactivator-3
T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORγt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-β/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORγt-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for RORγt-dependent gene expression in Th17 cell-driven autoimmune diseases.
Institute for Systems Biology
Tanaka, Kentaro; Martinez, Gustavo J; Yan, Xiaowei; Long, Weiwen; Ichiyama, Kenji; Chi, Xinxin; Kim, Byung-Seok; Reynolds, Joseph M; Chung, Yeonseok; Tanaka, Shinya; Liao, Lan; Nakanishi, Yoichi; Yoshimura, Akihiko; Zheng, Pan; Wang, Xiaohu; Tian, Qiang; Xu, Jianming; O'Malley, Bert W; and Dong, Chen, "Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3." (2018). All Publications. 147.