title: Immune complexes and IFN-gamma 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-gamma 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-gamma 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.
authors.affiliation: Department of Medicine, New Bellevue 16N28, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. reissa01@popmail.med.nyu.edu
authors.forename: A B
authors.initials: AB
authors.lastname: Reiss
authors.forename: N W
authors.initials: NW
authors.lastname: Awadallah
authors.forename: S
authors.initials: S
authors.lastname: Malhotra
authors.forename: M C
authors.initials: MC
authors.lastname: Montesinos
authors.forename: E S
authors.initials: ES
authors.lastname: Chan
authors.forename: N B
authors.initials: NB
authors.lastname: Javitt
authors.forename: B N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D000936:Antigen-Antibody Complex / Q000494:pharmacology* / Q000502:physiology; D001011:Aorta; D015153:Blotting, Western; D002352:Carrier Proteins; D002460:Cell Line; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism; D015922:Complement C1q / Q000276:immunology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors; D006900:Hydroxylation; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000276:immunology; D008264:Macrophages / Q000201:enzymology*; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D009000:Monocytes / Q000201:enzymology; D011506:Proteins / Q000276:immunology / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011951:Receptors, Complement / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000936:Antigen-Antibody Complex; C087299:C1QBP protein, human; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012333:RNA, Messenger; D011951:Receptors, Complement; C007105:c1q-binding proteins; C032402:complement 1q receptor; D015922:Complement C1q; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase