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Protective Effect of IL-18 on Kainate- and IL-1β-Induced Cerebellar Ataxia in Mice¹

Tsugunobu Andoh^*, Hiroyuki Kishi^2,, Kazumi Motoki, Kenji Nakanishi, Yasushi Kuraishi^* and Atsushi Muraguchi

^* Department of Applied Pharmacology and Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; and Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan

The pathogenesis of sporadic cerebellar ataxia remains unknown. In this study, we demonstrate that proinflammatory cytokines, IL-18 and IL-1β, reciprocally regulate kainate-induced cerebellar ataxia in mice. We show that systemic administration of kainate activated IL-1β and IL-18 predominantly in the cerebellum of mice, which was accompanied with ataxia. Mice deficient in caspase-1, IL-1R type I, or MyD88 were resistant to kainate-induced ataxia, while IL-18- or IL-18R -deficient mice displayed significant delay of recovery from ataxia. A direct intracerebellar injection of IL-1β-induced ataxia and intracerebellar coinjection of IL-18 counteracted the effect of IL-1β. Our data firstly show that IL-18 and IL-1β display differential direct regulation in kainate-induced ataxia in mice. Our results might contribute toward the development of a new therapeutic strategy for cerebellar ataxia in humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

² Address correspondence and reprint requests to Dr. Hiroyuki Kishi, Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630, Sugitani, Toyama, 930-0194 Japan. E-mail address: immkishi{at}med.u-toyama.ac.jp

³ Abbreviations used in this paper: IL-1ra, IL-1 receptor antagonist; IL-1RI, IL-1 receptor type I.

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