Attenuation of temporary focal cerebral ischemic injury in the mouse following transfection with interleukin-1 receptor antagonist.
The proinflammatory cytokine interleukin-1 beta (IL-1beta) is thought to play an important role in the stimulation of the inflammatory response following ischemia and reperfusion. This study investigated the inflammatory effect of IL-1beta during transient focal cerebral ischemia and reperfusion in the mouse transduced with the interleukin-1 receptor antagonist (IL-1ra) gene. An adenoviral vector encoding, either the human IL-1ra gene (AdRSVIL-1ra) or the LacZ gene (AdRSVlacZ) or normal saline, were injected into the right lateral ventricles of adult CD-1 mice (n=96). Five days later, the mice received 1 h temporary middle cerebral artery occlusion (tMACAO) followed by 23 h reperfusion. Cerebral blood flow (CBF), infarct volume, blood-brain barrier (BBB) permeability, and the number of intracellular adhesion molecule-1 positive vessels were measured to determine the effect of IL-1beta during postischemic reperfusion. Infarct volume in the AdRSVIL-1ra-transduced mice was markedly reduced compared to the AdRSVlacZ-transduced and saline-injected mice (36.0+/-5.3 mm(3) vs. 60.0+/-6.2 mm(3), 69. 5+/-6.3 mm(3), after 23 h of reperfusion, n=6-8 per group, p<0.05). BBB disruption and intracellular adhesion molecule-1 expression (135+/-23 vs. 311+/-40 and 357+/-51, n=6-8 per group, p<0.05) in the AdRSVIL-1ra-transduced mice were also less than that of the AdRSVlacZ-transduced and saline-injected mice. Our studies demonstrated that overexpression of IL-1ra in the mouse brain can downregulate intracellular adhesion molecule-1 expression both in the cortex and basal ganglia, which suggests that IL-1beta may play an important role in the activation of the inflammatory response during focal cerebral ischemia by promoting leukocyte adhesion to endothelial cells. The decrease of BBB disruption in AdRSVIL-1ra-transduced mice suggests that the endothelial cells may be a target for IL-1beta during postischemic reperfusion.
Yang
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GY
Department of Surgery (Neurosurgery), School of Medicine, University of Michigan, 5550 Kresge I/0532, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0532, USA. guoyuan@umich.edu
Mao
Y
Y
Zhou
L F
LF
Ye
W
W
Liu
X H
XH
Gong
C
C
Lorris Betz
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation; D016207:Cytokines / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D053590:Interleukin 1 Receptor Antagonist Protein; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*; D012795:Sialoglycoproteins / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D012795:Sialoglycoproteins; D018799:Intercellular Adhesion Molecule-1