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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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
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
, IL-1ß, IL-1 and IL-1ß (IL-1) or IL-1Ra genes. IL-1/ß double-deficient (IL-1–/–) mice exhibited significant resistance to EAE induction with a significant reduction in disease severity, while IL-1–/– 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-
and IL-17 production and proliferation were reduced in IL-1–/– T cells upon stimulation with MOG, while IFN-, IL-17 and tumor necrosis factor- 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
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