The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/2/719/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 4, February 15, 1999 719-727

Articles

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

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

From the * Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; and the {ddagger} 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.

Key Words: cerebral ischemia • interferon regulatory factor 1 null mice • gene expression • neuroprotection • reverse transcription polymerase chain reaction

Address correspondence to Costantino Iadecola, Department of Neurology, University of Minnesota, Box 295 UMHC, 420 Delaware St. South-East, Minneapolis, MN 55455. Phone: 612-624-1902; Fax: 612-625-7950; E-mail: iadec001{at}tc.umn.edu

The excellent editorial assistance of Ms. Karen MacEwan is acknowledged. We wish to thank Ms. Diana Miller for technical assistance.

Abbreviations used: CBF, cerebral blood flow; HPRT, hypoxanthine-guanine phosphoribosyl transferase; IRF-1, interferon regulatory factor 1, iNOS, inducible nitric oxide synthase; MCA, middle cerebral artery; NO, nitric oxide.


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