S1742 Rectal Administration of Tranilast Ameliorated Acute Colitis in Mice Through Increased Expression of Heme Oxygenase-1

Abstract

BACKGROUND: Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, a mast cell stabilizer, has been empirically used for IBD in Japan. The mechanism of tranilast in the improvement of IBD, however, has not yet been clearly delineated, and requires further investigation. Recently, heme oxygenase (HO)-1 has attracted attention in the pro-inflammationmechanism of tranilast. Aim: To investigate the role of tranilast for the treatment of IBD, and elucidated the mechanism and involvement of HO-1 in this effect, we administered tranilast intrarectally to dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Colitis was induced in C57BL/6(B6) mice by adding 3% DSS in drinking water ad libium for 5 days. Tranilast was administered by enema on day 0, day 2, and day 4 after induction of colitis. The disease activity index (DAI) and degree of colon injury were determined to know the clinical course of colitis. Toluidine blue staining was carried out to identify the mast cell. Staining for HO1 with immunofluorescence to evaluate the expression of HO-1 in the colon. Total RNA was extracted from colon specimens with quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Tranilast ameliorated DSS colitis clinically and pathologically with decreased number and degranulation of mast cells in the colon of DSS colitis. mRNA expression was increased for tumor necrosis factor(TNF)-α, interferon(IFN)-γ, interleukin (IL)-6, and decreased that for IL-10 in the colon of DSS colitis. In contrast, tranilast markedly decreased expression of mRNAs for the proinflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased HO-1 expression on colonic epithelial cells as well as on colon infiltrating cells of DSS colitis. CONCLUSION: Tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD.