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The Journal of Neuroscience, August 1, 2001, 21(15):5528-5534

Role of IL-1 and IL-1 in Ischemic Brain Damage

H. Boutin¹, R. A. LeFeuvre¹, R. Horai², M. Asano³, Y. Iwakura², and N. J. Rothwell¹

¹ School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, ² Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, 108-8639, Japan, and ³ Institute for Experimental Animals, Faculty of Medicine, Kanazawa University, Kanazawa 920-8640, Japan

The cytokine interleukin-1 (IL-1) has been strongly implicated in the pathogenesis of ischemic brain damage. Evidence to date suggests that the major form of IL-1 contributing to ischemic injury is IL-1 rather than IL-1, but this has not been tested directly.

The objective of the present study was to compare the effects of transient cerebral ischemia [30 min middle cerebral artery occlusion (MCAO)] on neuronal injury in wild-type (WT) mice and in IL-1, IL-1, or both IL-1 and IL-1 knock-out (KO) mice.

Mice lacking both forms of IL-1 exhibited dramatically reduced ischemic infarct volumes compared with wild type (total volume, 70%; cortex, 87% reduction). Ischemic damage compared with WT mice was not significantly altered in mice lacking either IL-1 or IL-1 alone. IL-1 mRNA, but not IL-1 or the IL-1 type 1 receptor, was strongly induced by MCAO in WT and IL-1 KO mice.

Administration (intracerebroventricularly) of recombinant IL-1 receptor antagonist significantly reduced infarct volume in WT (-32%) and IL-1 KO (-48%) mice, but had no effect on injury in IL-1 or IL-1/ KO mice.

These data confirm that IL-1 plays a major role in ischemic brain injury. They also show that chronic deletion of IL-1 or IL-1 fails to influence brain damage, probably because of compensatory changes in the IL-1 system in IL-1 KO mice and changes in IL-1-independent mediators of neuronal death in IL-1 KO mice.

Key words: interleukin-1; cytokines; stroke; brain; knock-out; mouse

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21155528-07$05.00/0

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