Lay Summary

The etiology of inflammatory bowel diseases (IBD) is still unclear; data from the last 5 years have provided evidence for genetic predispositions, however. Great efforts have been made to elucidate the pathogenesis of IBD, although some key problems remain unsolved. In particular, relatively few studies have performed extensive analysis of patient material in IBD to identify crucial factors for perpetuation and prognosis of IBD. Crucial mediators of inflammation are produced by lymphocytes and other cells of the mucosal immune system.

 

We will analyze the role of potentially important key regulatory factors in cells of the mucosal immune system (T cells) that may be important for the beginning of inflammation, but also during the course of chronic IBD. In this study, we will focus on a factor which regulates function of T cells and which is over-produced in IBD, thus leading to over-production of mediators of inflammation. This factor is called IRF-4.

 

Because our analyses showed that IRF-4 is over-expressed in immune cells from patients suffering from Crohn’s disease and ulcerative colitis (Mudter et al. JCI 2008), we tried to prove that this factor is functionally relevant. Therefore, we induced colitis in several mice colitis models. We also used genetically altered mice. These mice were not able to produce any IRF-4. Interestingly, these so called IRF-4 knockout mice were protected from colitis suggesting that IRF-4 has an important functional role in chronic inflammation. In further studies we want to get deeper insights in the functional role of this factor in humans. We will also characterize other factors of the IRF family to get information about potential synergistic effects of these factors.

 

Both approaches are sufficient to paint a picture of the importance of IRF molecules in IBD signaling including therapeutic options. Our studies will help to design markers for prognosis of IBD patients and to delineate novel target structures for therapy.