The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis.
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.
Weigmann
Benno
B
Institute of Molecular Medicine, Johanes Gutenberg Univeristy, 55131 Mainz, Germany.
Lehr
Hans A
HA
Yancopoulos
George
G
Valenzuela
David
D
Murphy
Andrew
A
Stevens
Sean
S
Schmidt
Jan
J
Galle
Peter R
PR
Rose-John
Stefan
S
Neurath
Markus F
MF
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010081:Oxazolone / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D018793:Interleukin-13; D020381:Interleukin-17; D015850:Interleukin-6; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D010081:Oxazolone