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

Allison B Reiss,Nahel W Awadallah,Sandeep Malhotra,M Carmen Montesinos,Edwin S.L Chan,Norman B Javitt,Bruce N Cronstein

doi:10.1016/s0022-2275(20)31518-2

Allison B Reiss, Nahel W Awadallah + Show 5 more

Open Access

PDF Available

https://doi.org/10.1016/s0022-2275(20)31518-2

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

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-γ 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-γ 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. B., N. W. Awadallah, S. Malhotra, M. C. Montesinos, E. S. L. Chan, N. B. Javitt, and B. N. Cronstein. Immune complexes and IFN-γ decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages.

Highlights

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
To determine whether cholesterol 27-hydroxylase is regulated in macrophages by immune reactants, we studied expression of mRNA for the enzyme in THP-1 cells, a monocytoid cell line
We demonstrate that IFN-␥, but not other cytokines such as IL-1 and tumor necrosis factor (TNF)-␣, down-regulates cholesterol 27-hydroxyase mRNA and protein

Summary

Introduction

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. 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. It has recently been appreciated that the metabolism of cholesterol to 27-hydroxycholesterol by endothelial cells and macrophages in the arterial wall by the action of the mitochondrial P450 enzyme cholesterol 27-hydroxylase may constitute one of the first lines of defense in the prevention of atherosclerosis [8,9,10,11,12].

Methods

Results

Conclusion