International Immunology Advance Access originally published online on April 1, 2008
International Immunology 2008 20(6):753-762; doi:10.1093/intimm/dxn033
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Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice
1 Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
2 Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
3 Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
4 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
5 Department of Pathology
6 Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
7 Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
Correspondence to: T. Naka; E-mail: tnaka{at}nibio.go.jp
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-
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-. 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-, 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-+ 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- 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-/STAT1 signaling and by subsequently regulating Treg cell development.
Keywords: DSS-induced colitis, IBD, IFN-, SOCS-1, Treg
Transmitting editor: T. Watanabe
Received 4 October 2007, accepted 29 February 2008.