J. Exp. Med., Volume 189, Number 4, February 15, 1999 719-727

The Transcription Factor Interferon Regulatory Factor 1 Is Expressed after Cerebral Ischemia and Contributes to Ischemic Brain Injury

By Costantino Iadecola,^* Cindy A. Salkowski, Fangyi Zhang,^* Tracy Aber,^* Masao Nagayama,^* Stefanie N. Vogel, and M. Elizabeth Ross^*

From the ^* Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; and the  Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

The transcription factor interferon regulatory factor 1 (IRF-1) is involved in the molecular mechanisms of inflammation and apoptosis, processes that contribute to ischemic brain injury. In this study, the induction of IRF-1 in response to cerebral ischemia and its role in ischemic brain injury were investigated. IRF-1 gene expression was markedly upregulated within 12 h of occlusion of the middle cerebral artery in C57BL/6 mice. The expression reached a peak 4 d after ischemia (6.0 ± 1.8-fold; P < 0.001) and was restricted to the ischemic regions of the brain. The volume of ischemic injury was reduced by 23 ± 3% in IRF-1^+/ and by 46 ± 9% in IRF-1^/ mice (P < 0.05). The reduction in infarct volume was paralleled by a substantial attenuation in neurological deficits. Thus, IRF-1 is the first nuclear transacting factor demonstrated to contribute directly to cerebral ischemic damage and may be a novel therapeutic target in ischemic stroke.

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