Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor

Kyoko Oh-Oka; Yuko Kojima; Koichiro Uchida; Kimiko Yoda; Kayoko Ishimaru; Shotaro Nakajima; Jun Hemmi; Hiroshi Kano; Yoshiaki Fujii-Kuriyama; Ryohei Katoh; Hiroyuki Ito; Atsuhito Nakao

doi:10.1016/j.jcmgh.2017.03.010

Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor

Cell Mol Gastroenterol Hepatol. 2017 Apr 11;4(1):135-151. doi: 10.1016/j.jcmgh.2017.03.010. eCollection 2017 Jul.

Authors

Kyoko Oh-Oka¹, Yuko Kojima², Koichiro Uchida³, Kimiko Yoda⁴, Kayoko Ishimaru¹, Shotaro Nakajima¹, Jun Hemmi⁵, Hiroshi Kano⁵, Yoshiaki Fujii-Kuriyama⁶, Ryohei Katoh⁴, Hiroyuki Ito⁵, Atsuhito Nakao^{1

3}

Affiliations

¹ Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
² The Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University School of Medicine, Tokyo, Japan.
³ Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
⁴ Department of Pathology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
⁵ Food Science Research Laboratories, Division of Research and Development, Meiji Co, Ltd, Kanagawa, Japan.
⁶ Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Background & aims: Mesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4⁺ Foxp3⁺ 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)-β 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-β in the colon in an AhR-dependent manner and blockade of TGF-β 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-β activation.

Keywords: AhR, aryl hydrocarbon receptor; Aryl Hydrocarbon Receptor; BM, bone marrow; DSS, dextran sodium sulfate; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; LPL, lamina propria lymphocytes; MLN, mesenteric lymph nodes; Mesalamine; PBS, phosphate-buffered saline; Q-PCR, quantitative polymerase chain reaction; RPMI, Roswell Park Memorial Institute; Regulatory T Cells; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TGF, transforming growth factor; TGF-β; TNF, tumor necrosis factor; Tregs, regulatory T cells; WT, wild-type; XRE, xenobiotic responsive element; mAb, monoclonal antibody.