title: Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice.
abstract: Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract. Although the etiology and pathogenesis of IBD remain unknown, pro-inflammatory cytokines including IFN-gamma play an important role in the development of IBD. Suppressor of cytokine signaling-1 (SOCS-1) is a crucial inhibitor of cytokine signaling, particularly of IFN-gamma. In this study, we investigated the role of SOCS-1 in the development of murine dextran sulfate sodium (DSS)-induced colitis, a model of colitis resembling human IBD. SOCS-1 heterozygous (SOCS-1(+/-)) and wild-type (WT) mice were given 3% DSS dissolved in drinking water for 5 days. Activation and expression of signal transducers and activators of transcription (STAT) in colonic tissues were assessed by western blot analysis. The expression of CD4, IFN-gamma, IL-4, IL-17 and Forkhead box P3 (Foxp3) in colonic lamina propria lymphocytes was analyzed by flow cytometry and cytokine concentrations in serum were measured. DSS-treated SOCS-1(+/-) mice developed more severe colitis than DSS-treated WT mice. Enhanced activation of STAT1, a higher ratio of CD4(+)IFN-gamma(+) T cells and a lower frequency of Foxp3(+) regulatory T (Treg) cells, were observed in the colon of DSS-treated SOCS-1(+/-) mice compared with DSS-treated WT mice. DSS-treated SOCS-1(+/-) mice showed higher levels of IFN-gamma in sera than did DSS-treated WT mice. Furthermore, T cell-specific SOCS-1-conditional knockout mice developed more severe colitis than control mice after DSS administration. Our findings suggest that SOCS-1, particularly in T cells, prevents the development of DSS-induced colitis in mice by inhibiting IFN-gamma/STAT1 signaling and by subsequently regulating Treg cell development.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Horino
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Terabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Soma
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Chinen
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000096:biosynthesis*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D016264:Dextran Sulfate