The transcription factor interferon regulatory factor-4 controls experimental colitis via IL-6/sIL-6R

Abstract

The interferon regulatory factor-4 (IRF4) is a central player in T cell regulation and differentiation. In the present study, we assessed the functional role of IRF4 in the immunopathogenesis of experimental colitis. As our previous data have shown, the number of IRF4 expressing mucosal T cells from IBD patients is increased compared with control patients. Consistently, adoptive transfer of wild-type but not IRF-4 deficient T cells resulted in severe colitis in reconstituted RAG deficient mice. Furthermore, IRF-4 knockout mice were protected from T cell dependent chronic intestinal inflammation in TNBS- and oxazolone-induced colitis and this finding was associated with reduced mucosal production of IL-6 and IL-17 in IRF4-/- mice as compared to wild-type control mice. The protective effect of IRF4 deficiency could be abrogated by systemic administration of rIL-6 or IL-6/sIL-6R (hyper IL-6). Subsequent studies showed that IRF4 is required for IL-6 production by mucosal T cells thereby controlling T cell activation and survival. Taken together, our data suggest that IRF4 is a key regulator of mucosal immune homeostasis via Th17 cells and highlight its potential as a therapeutic target in inflammatory bowel diseases.