Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice.
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.
Horino
Jiro
J
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Fujimoto
Minoru
M
Terabe
Fumitaka
F
Serada
Satoshi
S
Takahashi
Tsuyoshi
T
Soma
Yoshihito
Y
Tanaka
Kentaro
K
Chinen
Takatoshi
T
Yoshimura
Akihiko
A
Nomura
Shintaro
S
Kawase
Ichiro
I
Hayashi
Norio
N
Kishimoto
Tadamitsu
T
Naka
Tetsuji
T
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
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