Role of Isoprenylcysteine Carboxyl Methyltransferase in Tumor Necrosis Factor-α Stimulation of Expression of Vascular Cell Adhesion Molecule-1 in Endothelial Cells

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Abstract
We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells with N-acetyl-S-farnesyl-l-cysteine (AFC) or N-acetyl-S-geranylgeranyl-l-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-α (TNF-α) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-α stimulation of the cells significantly increased the met...