Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma.
The Th1-derived cytokine gamma interferon, IFN-gamma, is present within the microenvironment of an atheromatous lesion and likely contributes to lesion progression through macrophage activation. While the inflammatory effects of IFN-gamma are well known, the role of this cytokine in cholesterol metabolism in macrophage derived foam cells is unclear. In the present study, the incubation of foam cells with IFN-gamma resulted in the reduction of HDL(3)-mediated cholesterol efflux. The decrease in cholesterol efflux was not observed with other macrophage-activating factors as colony-stimulating factors failed to demonstrate a similar effect. The reduction in cholesterol efflux was independent of apoE synthesis or SR-BI expression and was associated with a redistribution of intracellular cholesterol with an increase in cholesteryl ester accumulation. The increase in the esterified pool, primarily in cholesterol eicosapentadenoate, docosapentaenoate, arachidonate, and linoleate was associated with a 2-fold increase in acyl-CoA:cholesterol-O-acyltransferase, ACAT, activity and message without any change in neutral cholesteryl ester hydrolase activity. While CD36 message was reduced in IFN-gamma-treated foam cells, the ability to reverse the decrease in efflux by the ACAT inhibitor A58035 in a dose-dependent manner suggests that the IFN-gamma effect on efflux is primarily through the modulation of ACAT expression. Therefore, in addition to its inflammatory effects, IFN-gamma can contribute to the progression of an atherosclerotic lesion by altering the pathway of intracellular cholesterol trafficking in macrophage derived foam cells.
Panousis
C G
CG
Division of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Zuckerman
S H
SH
D001483:Base Sequence; D001692:Biological Transport; D018955:CD36 Antigens; D008076:Cholesterol, HDL / Q000378:metabolism*; D017931:DNA Primers; D004790:Enzyme Induction; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008262:Macrophage Activation; D008565:Membrane Proteins; D011971:Receptors, Immunologic / Q000378:metabolism; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D018955:CD36 Antigens; D008076:Cholesterol, HDL; D017931:DNA Primers; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D007371:Interferon-gamma; D002785:Sterol O-Acyltransferase