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Med Sci Monit. 2004 Nov;10(11):BR420-5. Epub 2004 Oct 26.

Interferon-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages.

Author information

1
Department of Vascular Biology, Winthrop-University Hospital, Mineola, NY 11501, USA. areiss@winthrop.org

Abstract

BACKGROUND:

Cholesterol 27-hydroxylase, an enzyme expressed at high levels by human monocytes/macrophages, provides a first line of defense against the development of atherosclerosis. Prior studies have suggested that the cytokine interferon-gamma (IFN-gamma) promotes atherosclerosis. We therefore examined the effect of IFN-g on macrophage foam cell formation and on expression of the anti-atherogenic 27-hydroxylase in THP-1 human monocytes/macrophages.

MATERIAL/METHODS:

THP-1 monocytes and acetylated LDL-treated THP-1 macrophages were incubated in the presence or absence of IFN-gamma (500 U/ml) with or without the addition of IFN- gamma receptor blocking or neutralizing antibody. Foam cell formation was quantified based on percentage of macrophages harboring oil red O-stained globules. Cellular mRNA and protein were isolated. 27-Hydroxylase message was measured by RT-PCR and 27-hydroxylase protein by immunoblot.

RESULTS:

IFN-gamma -treated THP-1 macrophages exhibit increased foam cell transformation compared to untreated cells under cholesterol loading conditions. IFN-gamma-promoted foam cell formation is abolished by pre-treatment with either IFN-gamma neutralizing or IFN-gamma receptor blocking antibody. IFN-gamma diminishes cholesterol 27-hydroxylase expression in THP-1, and this IFN-gamma -induced downregulation is prevented by pre-treating the cultured cells with either IFN-gamma neutralizing or IFN-gamma receptor blocking antibody.

CONCLUSIONS:

Imbalances in cellular cholesterol flux within macrophages lead to formation of lipid-laden foam cells, a critical step in the pathogenesis of atherosclerosis. We have demonstrated that IFN-gamma, acting through the IFN-gamma receptor, decreases expression of 27-hydroxylase and increases propensity to foam cell formation in the cell line THP-1. These observations suggest that one mechanism by which IFN-g promotes atherosclerosis may involve affecting expression of cholesterol 27-hydroxylase, a cholesterol homeostatic protein.

PMID:
15507847
[Indexed for MEDLINE]

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