title: Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells.
abstract: Inflammatory bowel disease (IBD) represents a group of chronic inflammatory diseases characterized by inflammation and relapsing gastrointestinal disorders. Recent studies have shown that Th17 cells, which are well known as key mediators of chronic inflammation, have a pivotal role in onset and development of IBD in humans and mice, alike. In recent years, it has been reported that IL-27, which is an IL-12-related heterodimeric cytokine consisting of EBI3 and p28 subunits, act directly on naive T cells to suppress the differentiation of Th17 cells. However, effects of exogenous IL-27 on the IBD are not well elucidated. To clarify the suppressive effect of IL-27 treatment on IBD, we applied the flexible linking method to EBI3 and p28 subunits and generated a single-chain human IL-27 (scIL-27). scIL-27 inhibited xenogenic mouse Th17 cell differentiation in vitro, indicating that scIL-27 also acts in mouse immune systems. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse acute colitis model, subcutaneous scIL-27 treatment significantly improved the colon length, extent of necrosis, and ulceration and thickened epithelium and several pathological scores in a dose-dependent manner. scIL-27 clearly suppressed several inflammatory cytokines, including IL-17, in inflamed colon, except for anti-inflammatory cytokine IL-10. The mesenteric lymph node cells from scIL-27-treated mice also exhibited a reduced inflammatory response and, furthermore, a lower population of Th17 cells than those of PBS-treated mice. Finally, we showed the therapeutic efficacy of scIL-27 on TNBS-induced colitis even after active colitis was established. These results suggest new possible therapeutic approaches for IBD, including disorders such as Crohn's disease and ulcerative colitis.
authors.affiliation: Pharmaceutical Research Laboratory, Research Division, Nihon Pharmaceutical, Co. Ltd., Sumiyoshichou, Izumisano, Osaka, Japan. sasaoka@nihon-pharm.co.jp
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ito
authors.forename: Junji
authors.initials: J
authors.lastname: Yamashita
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakajima
authors.forename: Issei
authors.initials: I
authors.lastname: Tanaka
authors.forename: Masakuni
authors.initials: M
authors.lastname: Narita
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hara
authors.forename: Kaori
authors.initials: K
authors.lastname: Hada
authors.forename: Munehisa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Ohno
authors.forename: Takato
authors.initials: T
authors.lastname: Matsuo
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kaneshiro
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kenji
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D020381:Interleukin-17