THE INDUCTION OF ICAM-1 IN HUMAN CEREBROMICROVASCULAR ENDOTHELIAL-CELLS (HCEC) BY ISCHEMIA-LIKE CONDITIONS PROMOTES ENHANCED NEUTROPHIL HCEC ADHESION/

Ischemic brain injury is exacerbated by leukocyte infiltration and for mation of vasogenic edema. In this study we demonstrate that intercell ular adhesion molecule-1 (ICAM-1) is dramatically (3 to 15-fold) up-re gulated in human cerebromicrovascular endothelial cells (HCEC) by a 16 h exposure to the cytokine, IL-1 beta (50-200 u/ml), the phorbol este r, TPA (1-100 nM), or by simulated in vitro ischemia/reperfusion. Thes e treatments also significantly increased the adhesion of allogeneic n eutrophils to HCEC monolayers. Both IL-1 beta- and TPA-induced express ion of ICAM-1 and increased neutrophil adhesion to HCEC were inhibited by the transcriptional inhibitor, actinomycin D (AcD; 1-10 mu g/ml), and by an anti-ICAM-1 antibody (ICAM-1 Ab). By contrast, ischemia-indu ced neutrophil adhesion was only slightly affected by AcD and ICAM-1 A b alone, but it was abolished by the combination of anti-ICAM-1 and an ti-CD18 antibodies. The increase in surface expression of ICAM-1 and n eutrophil adhesion by IL-1 beta, TPA and ischemia were significantly r educed by the cyclo-oxygenase (COX) inhibitors, indomethacin (100-300 mu M) and dexamethasone (10-50 mu M). These results indicate that ICAM -1 expression in HCEC can lead to enhanced neutrophil adhesion and tha t COX activation in HCEC likely plays a role in the processes by which leukocyte adhesion and recruitment take place in the brain during inf lammation and ischemia in vivo.