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

Abstract

The enzyme cholesterol 27-hydroxylase, expressed by arterial endothelium and monocytes/macrophages, is one of the first lines of defense against the development of atherosclerosis. By catalyzing the hydroxylation of cholesterol to 27-hydroxycholesterol, which is more soluble in aqueous medium, the enzyme promotes the removal of cholesterol from the arterial wall. Prior studies have suggested that immune reactants play a role in the pathogenesis of atherosclerosis; we report here that immune reactants, IFN-␥ and immune complexes bound to C1q, but not interleukin-1 and tumor necrosis factor, diminish the expression of cholesterol 27-hydroxylase in human aortic endothelial cells, peripheral blood mononuclear cells, monocyte-derived macrophages, and the human monocytoid cell line THP-1. In addition, our studies demonstrate that immune complexes down-regulate cholesterol 27-hydroxylase only 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-␥ contributes to the pathogenesis of atherosclerosis and suggest a role for C1q receptors in the atherogenic process. Moreover, these observations suggest that one mechanism by which immune reactants contribute to the development of atherosclerosis is by down-regulating the expression of the enzymes required to maintain cholesterol homeostasis in the arterial wall. -Reiss, A

The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus?

“…24 Rabbit-derived immune complex directed against bovine serum albumin bound to human C1q can interact with cultured human aortic endothelium via the C1q receptor and has been shown to inhibit the enzyme cholesterol 27-hydroxylase, which is expressed in arterial endothelium and monocyte/macrophage cell lines. 25 This enzyme catalyses the hydroxylation of cholesterol to 27-hydroxycholesterol, which is more water-soluble and more easily removed from the arterial wall. This process contributes to reverse cholesterol transport (the transport of cholesterol from peripheral tissues to the liver) and protects against accumulation of lipid and development of plaque.…”

“…This process contributes to reverse cholesterol transport (the transport of cholesterol from peripheral tissues to the liver) and protects against accumulation of lipid and development of plaque. 25 The precise contribution, however, of immune complex-mediated endothelial injury to CVD in SLE remains to be determined.…”

The Role of Immune Complexes in Atherogenesis

“…The IC-C1q complex has been shown to bind to C1q receptors on the surface of endothelial cells and to stimulate the expression of adhesion molecules, intercellular and vascular cell adhesion molecule 1 on endothelial cells, 27 while downregulating the expression of the enzyme cholesterol 27-hydroxylase, which is expressed by arterial endothelium, monocytes, and macrophages. 28 Adhesion molecules promote the attachment and thus the recruitment of mononuclear cells to the arterial wall, 29 and it has been proposed that cholesterol 27-hydroxylase provides one of the first lines of defense against atherosclerosis by promoting the removal of cholesterol from the arterial wall. 30,31 Immune complexes of IgG with ox-LDL activate complement with the release of the complement activation product C3a.…”

Factors affecting SP-A-mediated phagocytosis in human monocytic cell lines

“…[24][25][26] These receptors may include Fc receptors, mannose receptors, and complement C1q receptors, all of which have been demonstrated to be expressed on THP-1 cells. [41][42][43] Interaction between these microbial surface components and the receptors on the phagocytic cells results in binding of the target by the phagocytic cell, followed by its internalization.…”