Homocysteine inhibits tumor necrosis factor-induced activation of endothelium via modulation of nuclear factor-kappa b activity

Homocystinuria is a metabolic disorder associated with an increased inciden ce of vascular disease. Here, we analyzed the effects of homocysteine on en dothelial cell activation that is a prerequisite for the recruitment of leu kocytes to sites of evolving atherosclerotic plaques. Exposure of human umb ilical vein endothelial cells to homocysteine alone did not modulate expres sion of the adhesion molecules E-selectin, intercellular adhesion molecule- 1 and vascular cell adhesion molecule-1, and the chemokines monocyte chemot actic protein-1 and interleukin-8. In contrast, tumor necrosis factor (TNF) -induced upregulation of these molecules was almost completely inhibited by homocysteine, but not by related thiol amino acids. Using electrophoretic mobility shift and reporter gene assays, the inhibitory effect of homocyste ine could be attributed to inhibition of DNA binding and transcriptional ac tivity of NF-KB. TNF-induced phosphorylation and degradation of I kappaB-al pha however, were not affected. Neither was NF-KB-independent activation of endothelial cells by interferon-gamma influenced by homocysteine. In summa ry, our data indicate that homocysteine alters the response to injury of en dothelial cells which may have fundamental impacts on mechanisms of leukocy te recruitment to sites of inflammation. Our findings might refer to a nove l pathway by which homocysteine is involved in vascular disorders associate d with homocystinuria. (C) 2001 Elsevier Science B.V. All rights reserved.