Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells

Cholesterol efflux is a fundamental process that serves to mitigate cholest erol accumulation and macrophage foam cell formation. Recently, we reported that cholesterol efflux to high density lipoprotein subfraction 3 was redu ced by interferon-gamma (IFN-gamma) and that this decrease was associated w ith an increase in acyl coenzyme A:cholesterol acyltransferase (ACAT) expre ssion. In the present study, although treatment of murine peritoneal macrop hages with IFN-gamma resulted in a 2-fold decrease in HDL-mediated choleste rol 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 ge ne responsible for the defect in Tangier disease. Consistent with the reduc tion in cholesterol and phospholipid efflux in Tangier fibroblasts, downreg ulation of ABC1 expression by IFN-gamma also resulted in reduced phosphatid ylcholine and sphingomyelin efflux to apolipoprotein A-I. Whereas foam cell s had a 3-fold increase in ABC1 mRNA, the decrease in ABC1 message levels b y IFN-gamma was observed in foam cells and control macrophages. This effect of IFN-gamma was independent of general macrophage activation (inasmuch as similar changes were not detected with granulocyte-macrophage colony-stimu lating factor) and was not observed with ether ABC transporters (inasmuch a s the expression of the transporter in antigen processing was upregulated L F-fold in these same cells). Therefore, by decreasing cholesterol efflux th rough pathways that include the upregulation of ACAT and the downregulation of ABC1, IFN-gamma can shift the equilibrium between macrophages and foam cells and thus impact the progression of an atherosclerotic lesion.