Interferon-gamma-mediated downregulation of cholesterol efflux and ABC1 expression is by the Stat1 pathway.
The pathological role of interferon-gamma (IFN-gamma) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ATP-binding cassette transporter 1(ABC1) message and protein levels were decreased 3- to 4-fold in foam cells by IFN-gamma. In the present study, the pathway by which IFN-gamma inhibited ABC1 expression was investigated with signal transducers and activators of transcription (Stat1) knockout mice. IFN-gamma-stimulated, wild-type, macrophage-derived foam cells, as previously reported, exhibited a decrease in cholesterol efflux and ABC1 expression as well as an increase in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, IFN-gamma treatment of foam cells from Stat1 knockout mice failed to demonstrate reductions in efflux or ABC1 expression at the message or protein levels, nor were there any increases in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, ABC1 mRNA expression in macrophages from Stat1 knockout mice could still be demonstrated to be increased by lipid loading with acetylated low density lipoprotein. Finally, Stat1-independent gene activation by IFN-gamma was intact in the Stat1 KO macrophages, inasmuch as IFN-gamma was shown to stimulate increases in interleukin-6 production in the Stat1 KO macrophages that were comparable to those observed in the wild-type macrophages. Therefore, Stat1 signaling is necessary and sufficient for the inhibitory effects of IFN-gamma on cholesterol efflux and ABC1 expression.
Wang
Xue-Qing
XQ
Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, Ind 46285, USA.
Panousis
Constantinos G
CG
Alfaro
M Leticia
ML
Evans
Glenn F
GF
Zuckerman
Steven H
SH
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000503:physiopathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology*; D005487:Foam Cells / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D002784:Cholesterol