title: Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis.
abstract: Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-β/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production.
authors.affiliation: Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa, Japan; Department of Gastroenterology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Imai
authors.affiliation: Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa, Japan; Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan. Electronic address: hozumi@is.icc.u-tokai.ac.jp.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa, Japan; Department of Regenerative Medicine, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Sumiyoshi
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yazawa
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirano
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Company Limited, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Company Limited, Osaka, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Higashi
authors.affiliation: Center for Matrix Biology and Medicine, Tokai University School of Medicine, Kanagawa, Japan; Department of Regenerative Medicine, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Gastroenterology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mine
mesh_terms: D000466:Alkadienes / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D003106:Colon / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005355:Fibrosis; D051379:Mice; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000466:Alkadienes; D000893:Anti-Inflammatory Agents; D016207:Cytokines; C546007:HSc025; D014302:Trinitrobenzenesulfonic Acid
keywords: 2,4,6-Trinitrobenzene sulfonic acid; Colorectal fibrosis; IFN-γ; Inflammatory bowel disease; TGF-β; YB-1