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The transcription factor interferon regulatory factor 1 is expressed after cerebral ischemia and contributes to ischemic brain injury.

Iadecola C, Salkowski CA, Zhang F, Aber T, Nagayama M, Vogel SN, Ross ME - J. Exp. Med. (1999)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA. iadec001@tc.umn.edu

ABSTRACT
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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(A) Time course of IRF-1 mRNA expression in mouse cerebral cortex after MCA occlusion. Levels of IRF-1 mRNA were determined by reverse transcription PCR in samples of cerebral cortex ipsilateral (□) or contralateral to the occluded MCA (n = 6–12/time point).  mRNA data were normalized to the housekeeping gene HPRT, and are  expressed as fold-induction (mean ± SEM) relative to unoperated mice.  Since no major differences in IRF-1 mRNA were observed in sham- operated mice killed 12 h and 1, 2, 4, and 7 d after sham operation (n =  1–2/time point), mRNA data from all sham-operated mice were averaged. After MCA occlusion IRF-1 mRNA was markedly upregulated in  the ischemic cortex but not contralaterally (*P < 0.05 from contralateral  side; Student's t test). (B) A representative Southern blot from the ischemic side of untreated, sham-operated, and MCA-occluded mice (n =  3/group) is shown. Analysis of mRNA for the housekeeping gene HPRT  showed no difference among groups in the level of expression (data not  shown; see also Fig. 2 A).
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Figure 1: (A) Time course of IRF-1 mRNA expression in mouse cerebral cortex after MCA occlusion. Levels of IRF-1 mRNA were determined by reverse transcription PCR in samples of cerebral cortex ipsilateral (□) or contralateral to the occluded MCA (n = 6–12/time point). mRNA data were normalized to the housekeeping gene HPRT, and are expressed as fold-induction (mean ± SEM) relative to unoperated mice. Since no major differences in IRF-1 mRNA were observed in sham- operated mice killed 12 h and 1, 2, 4, and 7 d after sham operation (n = 1–2/time point), mRNA data from all sham-operated mice were averaged. After MCA occlusion IRF-1 mRNA was markedly upregulated in the ischemic cortex but not contralaterally (*P < 0.05 from contralateral side; Student's t test). (B) A representative Southern blot from the ischemic side of untreated, sham-operated, and MCA-occluded mice (n = 3/group) is shown. Analysis of mRNA for the housekeeping gene HPRT showed no difference among groups in the level of expression (data not shown; see also Fig. 2 A).

Mentions: We first sought to determine if focal cerebral ischemia enhances IRF-1 mRNA expression. In C57BL/6 mice, MCA occlusion was associated with pronounced upregulation of IRF-1 mRNA in the postischemic brain (Fig. 1). IRF-1 mRNA expression was increased by 12 h and remained elevated 1–7 d after MCA occlusion (P < 0.05 from sham-operated mice; analysis of variance and Tukey's test). IRF-1 mRNA expression did not increase in the contralateral (nonischemic) cortex (P > 0.05) (Fig. 1). IRF-1 mRNA expression was reduced in IRF-1+/− mice and absent in IRF-1−/− mice (Fig. 2).


The transcription factor interferon regulatory factor 1 is expressed after cerebral ischemia and contributes to ischemic brain injury.

Iadecola C, Salkowski CA, Zhang F, Aber T, Nagayama M, Vogel SN, Ross ME - J. Exp. Med. (1999)

(A) Time course of IRF-1 mRNA expression in mouse cerebral cortex after MCA occlusion. Levels of IRF-1 mRNA were determined by reverse transcription PCR in samples of cerebral cortex ipsilateral (□) or contralateral to the occluded MCA (n = 6–12/time point).  mRNA data were normalized to the housekeeping gene HPRT, and are  expressed as fold-induction (mean ± SEM) relative to unoperated mice.  Since no major differences in IRF-1 mRNA were observed in sham- operated mice killed 12 h and 1, 2, 4, and 7 d after sham operation (n =  1–2/time point), mRNA data from all sham-operated mice were averaged. After MCA occlusion IRF-1 mRNA was markedly upregulated in  the ischemic cortex but not contralaterally (*P < 0.05 from contralateral  side; Student's t test). (B) A representative Southern blot from the ischemic side of untreated, sham-operated, and MCA-occluded mice (n =  3/group) is shown. Analysis of mRNA for the housekeeping gene HPRT  showed no difference among groups in the level of expression (data not  shown; see also Fig. 2 A).
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Figure 1: (A) Time course of IRF-1 mRNA expression in mouse cerebral cortex after MCA occlusion. Levels of IRF-1 mRNA were determined by reverse transcription PCR in samples of cerebral cortex ipsilateral (□) or contralateral to the occluded MCA (n = 6–12/time point). mRNA data were normalized to the housekeeping gene HPRT, and are expressed as fold-induction (mean ± SEM) relative to unoperated mice. Since no major differences in IRF-1 mRNA were observed in sham- operated mice killed 12 h and 1, 2, 4, and 7 d after sham operation (n = 1–2/time point), mRNA data from all sham-operated mice were averaged. After MCA occlusion IRF-1 mRNA was markedly upregulated in the ischemic cortex but not contralaterally (*P < 0.05 from contralateral side; Student's t test). (B) A representative Southern blot from the ischemic side of untreated, sham-operated, and MCA-occluded mice (n = 3/group) is shown. Analysis of mRNA for the housekeeping gene HPRT showed no difference among groups in the level of expression (data not shown; see also Fig. 2 A).
Mentions: We first sought to determine if focal cerebral ischemia enhances IRF-1 mRNA expression. In C57BL/6 mice, MCA occlusion was associated with pronounced upregulation of IRF-1 mRNA in the postischemic brain (Fig. 1). IRF-1 mRNA expression was increased by 12 h and remained elevated 1–7 d after MCA occlusion (P < 0.05 from sham-operated mice; analysis of variance and Tukey's test). IRF-1 mRNA expression did not increase in the contralateral (nonischemic) cortex (P > 0.05) (Fig. 1). IRF-1 mRNA expression was reduced in IRF-1+/− mice and absent in IRF-1−/− mice (Fig. 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA. iadec001@tc.umn.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus