Novel Genetic Tristetraprolin (TTP) Knock-in Mouse

Tristetraprolin (TTP) is the prototype member of a small family of RNA binding proteins that bind to specific types of AU-rich elements in the 3'UTRs of target mRNAs and promote their rapid turnover. One of the targets destabilized by TTP is Tumor necrosis factor alpha (TNF). TNF has long been a target of anti-inflammatory drug development, in which recombinant protein molecules based on TNF antibodies or TNF receptors have been used to bind directly to TNF and inactivate it. These therapies are very expensive because of their recombinant origin, require frequent injections because they are proteins, run the risk of producing antibodies to themselves, and have other problems. This invention describes using the newly discovered endogenous anti-inflammatory protein, TTP, for possible therapeutic development. The inventors generated a novel genetic knock-in mouse line called the TTP?ARE mice, where the entire AU rich region (ARE) in the 3'UTR of TTP mRNA was deleted from the mouse genome. These mice were almost completely protected from the development of collagen antibody-induced arthritis, a standard model of immune-mediated arthritis that involves many of the cytokine systems. This finding supports the concept that general increases in “whole body” TTP might have beneficial consequences in certain inflammatory diseases if they could be achieved therapeutically.