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on STAT3 and Smads1
* Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation and
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka;
Department of Internal Medicine and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan; and
Institute of Molecular Biotechnology, Vienna, Austria
Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4+ T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-
–/– background, suggesting that a large amount of IFN- in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-β enhanced retinoic acid receptor-related orphan receptor (ROR)-t expression and suppressed IFN- production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-β. Suppression of Th1 differentiation by TGF-β was impaired in SOCS1-deficient T cells. TGF-β-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-. Such impairment of TGF-β functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN- on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN--mediated STAT3 suppression, while other mechanism(s) will be involved in IFN--mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.
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1 This work was supported by special Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, the Mochida Memorial Foundation, the Yamanouchi Foundation of Research on Metabolic Disorders, the Takeda Science Foundation, the Kato Memorial Foundation, the Uehara Memorial Foundation, the Kanae Foundation for the Promotion of Medical Science, Suzuken Memorial Foundation, Japan Intractable Disease Research Foundation, and the Nakatomi Foundation.
2 Address correspondence and reprint requests to Dr. Akihiko Yoshimura, Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: yakihiko{at}bioreg.kyushu-u.ac.jp
3 Abbreviations used in this paper: RORt, retinoic acid receptor-related orphan receptor t; SOCS, suppressor of cytokine signaling; cKO, conditioned knockout; Ct, control; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; WT, wild type; m, mouse; h, human; Tg, transgenic; MEF, mouse embryonic cell.
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  J. Horino, M. Fujimoto, F. Terabe, S. Serada, T. Takahashi, Y. Soma, K. Tanaka, T. Chinen, A. Yoshimura, S. Nomura, et al. Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice Int. Immunol., April 1, 2008; (2008) dxn033v1. [Abstract] [Full Text] [PDF]
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