The first two authors contributed equally to the work.
IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo†
Article first published online: 8 FEB 2011
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 17, Issue 6, pages 1343–1358, June 2011
How to Cite
Mudter, J., Yu, J., Zufferey, C., Brüstle, A., Wirtz, S., Weigmann, B., Hoffman, A., Schenk, M., Galle, P. R., Lehr, H. A., Mueller, C., Lohoff, M. and Neurath, M. F. (2011), IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo. Inflamm Bowel Dis, 17: 1343–1358. doi: 10.1002/ibd.21476
M.F.N and J.M. supported by a grant from the “Stiftung Rheinland-Pfalz für Innovation” and the Broad Foundation (Broad Medical Program). M.L. was supported by the DFG (SFB TR22) and by the LOEWE grant Tumor and Inflammation.
- Issue published online: 10 MAY 2011
- Article first published online: 8 FEB 2011
- Manuscript Accepted: 2 AUG 2010
- Manuscript Received: 30 JUL 2010
- inflammatory bowel disease;
- Crohn's disease;
- T cells;
- Interferon regulatory factor 4
The transcription factor IRF4 is involved in several T-cell-dependent chronic inflammatory diseases. To elucidate the mechanisms for pathological cytokine production in colitis, we addressed the role of the IRF transcription factors in human inflammatory bowel disease (IBD) and experimental colitis.
IRF levels and cytokine production in IBD patients were studied as well as the effects of IRF4 deficiency in experimental colitis.
In contrast to IRF1, IRF5, and IRF8, IRF4 expression in IBD was augmented in the presence of active inflammation. Furthermore, IRF4 levels significantly correlated with IL-6 and IL-17 mRNA expression and to a lesser extent with IL-22 mRNA expression in IBD. To further explore the role of IRF4 under in vivo conditions, we studied IRF4-deficient and wildtype mice in experimental colitis. In contrast to DSS colitis, IRF4 deficiency was protective in T-cell-dependent transfer colitis associated with reduced RORα/γt levels and impaired IL-6, IL-17a, and IL-22 production, suggesting that IRF4 acts as a master regulator of mucosal Th17 cell differentiation. Subsequent mechanistic studies using database analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assays identified a novel IRF4 binding site in the IL-17 gene promoter. Overexpression of IRF4 using retroviral infection induced IL-17 production and IL-17 together with IL-6 induced RORγt expression.
IRF4 can directly bind to the IL-17 promotor and induces mucosal RORγt levels and IL-17 gene expression thereby controlling Th17-dependent colitis. Targeting of this molecular mechanism may lead to novel therapeutic approaches in human IBD. (Inflamm Bowel Dis 2011;)