Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 4, Issue 1, Pages 135-151Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2017.03.010
Keywords
Mesalamine; Aryl Hydrocarbon Receptor; TGF-beta; Regulatory T Cells
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Meiji Co, Ltd.
- Grants-in-Aid for Scientific Research [15H04864, 15K19607, 15K19573] Funding Source: KAKEN
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BACKGROUND & AIMS: Mesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4+ Foxp(3+) regulatory T cells (Tregs) play a potential role in suppressing IBD. This study determined whether the anti-inflammatory activity of mesalamine is related to Treg induction in the colon. METHODS: We examined the frequencies of Tregs in the colons of wild-type mice, mice deficient for aryl hydrocarbon receptor (AhR(-/-) mice), and bone marrow-chimeric mice lacking AhR in hematopoietic cells (BM-AhR(-/-) mice), following oral treatment with mesalamine. We also examined the effects of mesalamine on transforming growth factor (TGF)-beta expression in the colon. RESULTS: Treatment of wild-type mice with mesalamine increased the accumulation of Tregs in the colon and up-regulated the AhR target gene Cyp1A1, but this effect was not observed in AhR(-/-) or BM-AhR(-/-) mice. In addition, mesalamine promoted in vitro differentiation of naive T cells to Tregs, concomitant with AhR activation. Mice treated with mesalamine exhibited increased levels of the active form of TGF-beta in the colon in an AhR-dependent manner and blockade of TGF-beta signaling suppressed induction of Tregs by mesalamine in the colon. Furthermore, mice pretreated with mesalamine acquired resistance to dextran sodium sulfate-induced colitis. CONCLUSIONS: We propose a novel anti-inflammatory mechanism of mesalamine for colitis: induction of Tregs in the colon via the AhR pathway, followed by TGF-b activation.
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