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International Immunology Advance Access originally published online on January 13, 2006
International Immunology 2006 18(2):399-407; doi:10.1093/intimm/dxh379
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis

Taizo Matsuki1, Susumu Nakae2, Katsuko Sudo3, Reiko Horai4 and Yoichiro Iwakura

Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
1 Present address: ERATO Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Koto-ku, Tokyo 135-0064, Japan
2 Present address: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5176, USA
3 Present address: Animal Research Center, Tokyo Medical University, Sinjyuku-ku, Tokyo 160-8402, Japan
4 Present address: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA

Correspondence to: Y. Iwakura; E-mail: iwakura{at}ims.u-tokyo.ac.jp

IL-1 is a pro-inflammatory cytokine that plays an important role in inflammation and host responses to infection. We have previously shown that imbalances in the IL-1 and IL-1R antagonist (IL-1Ra) system cause the development of inflammatory diseases. To explore the role of the IL-1/IL-1Ra system in autoimmune disease, we analyzed myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in mice bearing targeted disruptions of the IL-1{alpha}, IL-1ß, IL-1{alpha} and IL-1ß (IL-1) or IL-1Ra genes. IL-1{alpha}/ß double-deficient (IL-1–/–) mice exhibited significant resistance to EAE induction with a significant reduction in disease severity, while IL-1{alpha}–/– or IL-1ß–/– mice developed EAE in a manner similar to wild-type mice. IL-1Ra–/– mice also developed MOG-induced EAE normally with pertussis toxin (PTx) administration. In contrast to wild-type mice, however, these mice were highly susceptible to EAE induction in the absence of PTx administration. We found that both IFN-{gamma} and IL-17 production and proliferation were reduced in IL-1–/– T cells upon stimulation with MOG, while IFN-{gamma}, IL-17 and tumor necrosis factor-{alpha} production and proliferation were enhanced in IL-1Ra–/– T cells. These observations suggest that the IL-1/IL-1Ra system is crucial for auto-antigen-specific T cell induction and contributes to the development of EAE.

Keywords: autoimmunity, cytokines, dendritic cells, knockout mouse, T cells

Transmitting editor: Okumura


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