Expression of intercellular adhesion molecule 1 (ICAM-1) is reduced in permanent focal cerebral ischemic mouse brain using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist

Our previous studies have demonstrated that overexpression of recombinant h uman interleukin-l receptor antagonist protein (IL-1ra) via gene transfer c an reduce ischemic brain injury. However, the mechanism of action of IL-1ra in ischemia is unclear. Since interleukin-l can up-regulate intercellular adhesion molecules in endothelium, the present study was designed to determ ine whether overexpression of the IL-1ra can reduce the expression of inter cellular adhesion molecule-1 (ICAM-1) after ischemic injury. Normal saline or adenovirus vector (1x10(9) particles) encoding the human IL-1ra gene (Ad .RSVIL-1ra) or the Escherichia coli LacZ gene (Ad.RSVlacZ) was injected int o the right lateral cerebral ventricle of adult CD-1 mice. After five days, permanent middle cerebral artery occlusion (MCAO) was achieved for 24 h us ing an intraluminal suture. Cerebral blood flow was monitored by transcrani al laser Doppler flowmetry to verify the occlusion. ICAM-1 protein was quan tified using Western blot analysis and localized using immunohistochemistry . After MCAO, surface blood flow in the ischemic hemisphere was decreased t o 9-11% of the baseline. There were fewer ICAM-1 positive vessels in the is chemic cortex of the Ad.RSVIL-1ra transfected mice than in the Ad.RSVlacZ t ransfected and saline treated mice (138 +/- 19 vs. 249 +/- 25, 284 +/- 22, p < 0.05). Western blot analysis shows that ICAM-1 protein decreased 50-60% in the Ad.RSVIL-1ra group compared to the other two groups. There were no significant differences in the numbers of positive vessels in the ischemic basal ganglia and contralateral hemisphere among the three groups. Our stud ies suggest that IL-1ra overexpression can down-regulate the expression of ICAM-1 in the ipsilateral cortex in ischemic mice. Interleukin-1 may play a n important role in the activation of inflammatory reaction during focal ce rebral ischemia by promoting leukocyte adhesion on the endothelium cells. ( C) 1999 Elsevier Science B.V. All rights reserved.