Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1565-1571
© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Interferon-
Induces Downregulation of Tangier Disease Gene (ATP-Binding-Cassette Transporter 1) in Macrophage-Derived Foam Cells
From the Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, Ind.
Correspondence to Steven H. Zuckerman, Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, IN 46285. E-mail Zuckerman_Steven{at}lilly.com
Abstract—Cholesterol
efflux is a fundamental process that serves to mitigate
cholesterol accumulation and macrophage foam cell
formation. Recently, we reported that cholesterol efflux to
high density lipoprotein subfraction 3 was reduced by interferon-
(IFN-) and that this decrease was associated with an increase in
acyl coenzyme A:cholesterol acyltransferase (ACAT)
expression. In the present study, although treatment of murine
peritoneal macrophages with IFN- resulted in a 2-fold
decrease in HDL-mediated cholesterol efflux, efflux to
lipid-free apolipoprotein A-I was reduced >4-fold and approached basal
levels. This decrease was associated with a 3- to 4-fold reduction in
ATP-binding-cassette transporter 1 (ABC1) mRNA content, the gene
responsible for the defect in Tangier disease. Consistent with
the reduction in cholesterol and phospholipid efflux in
Tangier fibroblasts, downregulation of ABC1 expression by IFN- also
resulted in reduced phosphatidylcholine and sphingomyelin efflux to
apolipoprotein A-I. Whereas foam cells had a 3-fold increase in ABC1
mRNA, the decrease in ABC1 message levels by IFN- was observed in
foam cells and control macrophages. This effect of IFN- was
independent of general macrophage activation (inasmuch as
similar changes were not detected with granulocyte-macrophage
colony–stimulating factor) and was not observed with other ABC
transporters (inasmuch as the expression of the transporter in antigen
processing was upregulated 4-fold in these same cells). Therefore, by
decreasing cholesterol efflux through pathways that include
the upregulation of ACAT and the downregulation of ABC1, IFN- can
shift the equilibrium between macrophages and foam cells and
thus impact the progression of an atherosclerotic lesion.
Key Words: interferon- • cholesterol efflux • apolipoprotein A-I • ATP-binding-cassette transporter 1
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