Scientific Abstract

In this study, we will focus on the functional role of Interferon-regulatory factors (IRFs) in patients with inflammatory bowel diseases (IBD). Currently 10 members of this family are known, although their function in the context of inflammatory diseases is not yet clear. In fact, there are little or no data concerning the involvement of IRFs in chronic inflammation such as IBD. In our initial experiments we found that IRF-4 was overexpressed in gut specimen of patients suffering from IBD as compared to control patients. IRF-4 was mainly localized in CD3 positive T cells as well as dendritic cells (DCs). Furthermore, we analyzed the role of IRF-4 in three models of experimental colitis. We found that IRF-4 knockout mice are protected from Oxazolone and TNBS-induced colitis. Furthermore, additional studies suggested that the transfer of IRF4 deficient CD4 CD45RBhigh T cells in immunodeficient RAG mice does not induce colitis indicating a key regulatory role of IRF4 in mucosal T cells.

 

We will study human gut specimens and blood cells. First, expression of IRF family members in IBD will be quantified by real-time PCR. Gut specimen of at least 100 IBD and 100 control patients will be collected and evaluated for IRF-4 expression and for the expression of other IRF`s (IRF-1, IRF-3, IRF-7). The correlation between the degree of inflammation, the local invasion of bacteria, the disease localization, the disease phenotype and the expression of IRFs in Crohn`s disease and ulcerative colitis will be analyzed. Subsequently, the cell types expressing IRFs in IBD will be determined including lamina propria T cells and dendritic cells. Furthermore, the functional role of IRF4 in such cells will be studied using retroviral overexpression and siRNA and antisense DNA mediated downregulation in IBD patients. Therefore, the results obtained could be used to determine the functional role of IRFs in IBD. Finally, we will assess activation of NF-kappaB and Ets transcription factors in lamina propria cells from control and IBD patients to understand the mechanism for transcriptional regulation of IRF gene expression in IBD.

 

These studies will allow the identification of candidate transcription factors of the IRF family that play a key regulatory role in IBD. Furthermore, these studies may help to design markers for prognosis of IBD patients and to delineate novel target structures for therapy.