Genetic deletion of AU-rich region in the tristetraprolin (TTP) transcript increases TTP stability and expression and provides protection against inflammatory diseases (INM1P.433)

Abstract Tristetraprolin (TTP) is an mRNA binding protein that binds to AU-rich elements (AREs) in the 3’-untranslated regions (3’UTR) of specific mRNAs, such as that encoding tumor necrosis factor (TNF), and increases their rate of mRNA turnover. TTP mRNA also contains AREs within its own 3’UTR that are partly responsible for its own rapid turnover. In the present study, we generated a novel TTP mouse line (TTPΔARE) with a 136 base deletion in the 3’UTR AU-rich region of TTP mRNA, and studied the effect of this genetic modification on the levels of TTP mRNA and protein, and susceptibility of the mice to experimentally-induced inflammatory conditions. TTP mRNA stability was found to be enhanced in TTPΔARE bone marrow-derived macrophages (BMDMs) and mouse embryonic fibroblasts (MEFs). TTP protein expression was increased, both in the basal state and upon LPS stimulation, in BMDMs, and in selected mouse tissues. LPS-induced expression of TTP target mRNAs, particularly Tnf and Il-1β, was significantly reduced in TTPΔARE BMDMs. Most importantly, TTPΔARE mice were almost completely protected from collagen antibody-induced arthritis, and exhibited significantly reduced inflammation in an imiquimod-induced model of psoriasis. These data suggest that increased levels of TTP can protect against some experimentally induced inflammatory diseases. They also raise the possibility that increasing TTP levels in man might be an attractive therapeutic approach in some inflammatory conditions.