Genetic deletion of an instability motif in the Tristetraprolin (TTP) transcript: Implications for the treatment of systemic inflammation

TTP is an RNA binding protein that binds to AU‐rich elements (AREs) in the 3’ untranslated regions of specific mRNAs such as TNFα leading to mRNA deadenylation and decay. Mice deficient in TTP develop a systemic inflammation characterized by erosive arthritis. This phenotype is almost completely due to an excess of TNFα, since the administration of anti‐TNFα antibodies can almost completely prevent the development of this phenotype. The TTP transcript also contains an ARE within its 3’UTR, which may be responsible for the extreme lability of TTP mRNA and we have recently demonstrated that TTP can use some of these sites to regulate its own expression. In this study, we used “knock in” technology to delete the ARE of the TTP mRNA from the mouse genome. Deleting the ARE of the TTP mRNA enhanced its stability as well as increased the levels of TTP protein. LPS induced expression of TNFα mRNA and protein was reduced in macrophages from TTPΔARE mice. In addition, LPS induction of other proinflammatory cytokine mRNAs, such as those encoding IL6 and IL1β, was also found to be significantly reduced. These results suggest that an attempt towards increasing TTP levels in cells could represent a novel therapeutic strategy in the treatment of inflammatory diseases. Moreover, TTPΔARE mice might represent a useful model system for examining the effects of modestly increased but normally regulated TTP levels in systemic inflammatory diseases.