Immune complexes and IFN-gamma decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages

The enzyme cholesterol 27-hydroxylase, expressed by arterial endothelium an d monocytes/macrophages, is one of the first lines of defense against the d evelopment of atherosclerosis. By catalyzing the hydroxylation of cholester ol to 27-hydroxycholesterol, which is more soluble in aqueous medium, the e nzyme promotes the removal of cholesterol from the arterial wall. Prior stu dies have suggested that immune reactants play a role in the pathogenesis o f atherosclerosis; we report here that immune reactants, IFN-gamma and immu ne complexes bound to C1q, but not interleukin-1 and tumor necrosis factor, diminish the expression of cholesterol 27-hydroxylase in human aortic endo thelial cells, peripheral blood mononuclear cells, monocyte-derived macroph ages, and the human monocytoid cell line THP-1. In addition, our studies de monstrate that immune complexes down-regulate cholesterol 27-hydroxylase on ly after complement fixation via interaction with the 126-kD C1qRp protein on endothelial cells and THP-1 cells. These results are consistent with the prior demonstration that IFN-gamma contributes to the pathogenesis of athe rosclerosis and suggest a role for C1q receptors in the atherogenic process . Moreover, these observations suggest that one mechanism by which immune r eactants contribute to the development of atherosclerosis is by down-regula ting the expression of the enzymes required to maintain cholesterol homeost asis in the arterial wall.