Abstract
TH17 cells have been extensively investigated in inflammation, autoimmune diseases, and cancer. The precise molecular mechanisms for TH17 cell regulation, however, remain elusive, especially regulation at the post-transcriptional level. Tristetraprolin (TTP) is an RNA-binding protein important for degradation of the mRNAs encoding several proinflammatory cytokines. With newly generated T cell-specific TTP conditional knockout mice (CD4CreTTPf/f), we found that aging CD4CreTTPf/f mice displayed an increase of IL-17A in serum and spontaneously developed chronic skin inflammation along with increased effector TH17 cells in the affected skin. TTP inhibited TH17 cell development and function by promoting IL-17A mRNA degradation. In a DSS-induced colitis model, CD4CreTTPf/f mice displayed severe colitis and had more TH17 cells and serum IL-17A compared with wild-type mice. Furthermore, neutralization of IL-17A reduced the severity of colitis. Our results reveal a new mechanism for regulating TH17 function and TH17-mediated inflammation post-transcriptionally by TTP, suggests that TTP might be a novel therapeutic target for the treatment of TH17-mediated diseases.