The Journal of Experimental Medicine
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Published online August 18, 2008
doi:10.1084/jem.20072484
The Journal of Experimental Medicine, Vol. 205, No. 9, 2099-2110
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Weigmann et al.
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ARTICLE

 The transcription factor NFATc2 controls IL-6–dependent T cell activation in experimental colitis

Benno Weigmann1, Hans A. Lehr2, George Yancopoulos3, David Valenzuela3, Andrew Murphy3, Sean Stevens3, Jan Schmidt5, Peter R. Galle6, Stefan Rose-John4, and Markus F. Neurath1,6

1 Institute of Molecular Medicine, Johanes Gutenberg Univeristy, 55131 Mainz, Germany
2 Institut Universitaire de Pathologie, Universite de Lausanne, CH-1011 Lausanne, Switzerland
3 Regeneron Pharmaceuticals, Tarrytown, NY 10591
4 Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany
5 Department of Surgery, University of Heidelberg, 69120 Heidelberg, Germany
6 Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany

CORRESPONDENCE Markus F. Neurath: neurath{at}1-med.klinik.uni-mainz.de

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell–dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6–dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.

Abbreviations used: AAD, amino-actinomycin D; CD, Crohn's disease; IBD, inflammatory bowel disease; LPMC, lamina propria mononuclear cell; NFAT, nuclear factor of activated T cells; UC, ulcerative colitis.

© 2008 Weigmann et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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