Homocysteine inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappa B dependent pathway

Cellular adhesion molecules play a pivotal role in the pathogenesis of athe rosclerosis by mediating the adherence of blood leukocytes. Since hyperhomo cysteinemia appears to be an independent risk factor for the development of atherosclerosis, in this study we investigated the effect of homocysteine on basal and TNF-alpha -induced expression of intercellular adhesion molecu le-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) on human umbilical-vein endothel ial cells. Incubation of endothelial cells with homocysteine resulted in do se-dependent reduction in TNF-alpha -induced (5 ng/ml) expression of VCAM-1 , E-selectin, and ICAM-1 (the latter less pronounced). This effect was foun d to be specific since other thiol compounds-cysteine and glutathione-did n ot mimic homocysteine activity, Homocysteine attenuated TNF-alpha -stimulat ed U-937 adhesion to the endothelial monolayer and reduced TNF-alpha -induc ed activation of the transcription factor NF-kappaB, indicating that NF-kap paB inhibition may play a role in inhibiting expression of adhesion molecul es in endothelial cells. (C) 2001 Academic Press.