INHIBITION OF 5-LIPOXYGENASE BLOCKS IL-1-BETA-INDUCED VASCULAR ADHESION MOLECULE-1 GENE-EXPRESSION IN HUMAN ENDOTHELIAL-CELLS

Inflammation is characterized by the recruitment of leukocytes and the ir subsequent migration from the vasculature into the tissue, where th ey often cause severe damage. Endothelial cells play a major role in t his cascade by expressing cell surface adhesion molecules, such as VCA M-1 and ICAM-1, and chemokines, in response to cytokines. Many of thes e genes are under the control of inflammatory response transcription f actors such as nuclear factor (NF)-kappa B. In this study, we examined the effects of 5-lipoxygenase inhibitors (nordihydroguaiaretic acid a nd AA861) on IL-1 beta-induced VCAM-1 gene expression in HUVECs. We de monstrated that 5-lipoxygenase inhibitors, but not cyclooxygenase inhi bitors, block IL-1 beta-induced VCAM-1 cell surface expression and pro moter activity. In transiently transfected HUVECs, NF-kappa B-dependen t gene expression was inhibited by 5-lipoxygenase inhibitors. These in hibitors did not block IL-1 beta-induced nuclear translocation of NF-k appa B, inhibitor of kappa B-alpha proteolytic degradation, or signifi cantly reduce phosphorylation of p65. These studies indicate that inhi bition of 5-lipoxygenase blocks cytokine-induced VCAM-1 gene expressio n by reducing the functional activity of NF-kappa B/Rel proteins in HU VECs.