Abstract
Intercellular adhesion molecule-1 (ICAM-1) in cerebral vascular endothelium induced by ischemic insult triggers leukocyte infiltration and inflammatory reaction. We investigated the mechanism of hypothermic suppression of ICAM-1 in a model of focal cerebral ischemia. Rats underwent 2 hours of middle cerebral artery occlusion and were kept at 37°C or 33°C during occlusion and rewarmed to normal temperature immediately after reperfusion. Under hypothermic condition, robust activation of extracellular signal-regulated kinase-1/2 (ERK1/2) was observed in vascular endothelium of ischemic brain. Hypothermic suppression of ICAM-1 was reversed by ERK1/2 inhibition. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in ischemic vessel was attenuated by hypothermia. STAT3 inhibitor suppressed ICAM-1 production induced by stroke. ERK1/2 inhibition enhanced phosphorylation and DNA binding activity of STAT3 in hypothermic condition. In this study, we demonstrated that hypothermic suppression of ICAM-1 induction is mediated by enhanced ERK1/2 activation and subsequent attenuation of STAT3 action.
Highlights
Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily and the principal ligand for leukocyte function-associated antigen-1 (LFA-1), a member of the integrin superfamily
To find out the evidence that extracellular signal-regulated kinase-1/2 (ERK1/2) pathway in the endothelium is related with ICAM-1 induction, we first investigated the effect of hypothermia on the activation of ERK1/2
We performed Western blot analysis and observed that ischemiainduced phosphorylated ERK1/2 level was significantly higher in hypothermia group than normothermia while total ERK1/2 was not affected by the temperature difference (Figure 2(a))
Summary
Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily and the principal ligand for leukocyte function-associated antigen-1 (LFA-1), a member of the integrin superfamily. ICAM-1/LFA-1 adhesion system assists leukocyte movement into the tissue. LFA-1positive leukocytes are induced to adhere to ICAM-1-positive endothelial surface [1, 2], and to pass through the basement membrane into the tissue [3, 4]. During reperfusion period of stroke, infiltrated leukocytes contribute to the secondary injury by producing toxic substances that damage the brain cells and disrupt the blood-brain barrier [9, 10]. Since ICAM-1 is an important factor of leukocyte infiltration and reperfusion injury in stroke, intervention of ICAM-1 induction has been a promising therapeutic strategy against stroke
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