Leppkes, M; Becker, C; Ivanov, I I; Hirth, S; Wirtz, S; Neufert, C; Pouly, S; Murphy, A J; Valenzuela, D M; Yancopoulos, G D; Becher, B; Littman, D R; Neurath, M F (2009). RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology, 136(1):257-267.
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BACKGROUND AND AIMS: IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation. METHODS: Using an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and RORgamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice. RESULTS: Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of RORgamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of RORgamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F. CONCLUSIONS: We have identified a crucial role of RORgamma-expressing Th17 cells in chronic intestinal inflammation. RORgamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target RORgamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Institute of Experimental Immunology|
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||12 Feb 2010 17:08|
|Last Modified:||28 Nov 2013 00:08|
|Citations:||Web of Science®. Times Cited: 145|
Scopus®. Citation Count: 159
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