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

  • Weigmann, Benno Institute of Molecular Medicine, Johanes Gutenberg Univeristy, 55131 Mainz, Germany
  • Lehr, Hans A. Institut Universitaire de Pathologie, Universite de Lausanne, CH-1011 Lausanne, Switzerland
  • Yancopoulos, George Regeneron Pharmaceuticals, Tarrytown, NY 10591
  • Valenzuela, David Regeneron Pharmaceuticals, Tarrytown, NY 10591
  • Murphy, Andrew Regeneron Pharmaceuticals, Tarrytown, NY 10591
  • Stevens, Sean Regeneron Pharmaceuticals, Tarrytown, NY 10591
  • Schmidt, Jan Department of Surgery, University of Heidelberg, 69120 Heidelberg, Germany
  • Galle, Peter R. Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany
  • Rose-John, Stefan Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany
  • Neurath, Markus F. Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany
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  • 2008-8-18
Published in:
  • Journal of Experimental Medicine. - Rockefeller University Press. - 2008, vol. 205, no. 9, p. 2099-2110
Immunology
Immunology and Allergy
English 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.
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  • English
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hybrid
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https://sonar.ch/global/documents/106648
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