Interferon-oy Inhibits Scavenger Receptor Expression

The scavenger receptor (ScR) mediates uptake of chemically modified low density lipoprotein (LDL) by human monocytederived macrophages. It is not down-regulated by high intracellular cholesterol levels, and exposure of macrophages to acetylated or oxidized LDL therefore leads to foam cell development. The hypothesis that this represents an important mechanism for intracellular cholesterol accumulation in atherosclerosis is supported by the finding of ScR expression in foam cells of atherosclerotic plaques. T lymphocytes are also present in such plaques and it is known that T cell products regulate macrophage activation. We have therefore studied the effect of interferon-'y (IFN'y), a lymphokine secreted by activated T lymphocytes, on the expression of ScR in human monocytederived macrophages. Binding and uptake of acetylated LDL were significantly reduced in macrophages exposed to recombinant IFNy or IFN-y-containing lymphocyte-conditioned media. Competition experiments showed that the IFNy-regulated binding and uptake of acetylated LDL was mediated via ScR. IFN'y exerted its effect on the saturable binding of acetylated LDL by reducing the number of cell surface binding sites without significantly affecting the affinity between acetylated LDL and its receptor. Northern analysis revealed that the type I ScR mRNA was significantly reduced in IFNy-treated cells. Finally, IFN'y treatment reduced intracellular cholesteryl ester accumulation and inhibited the development offoam cells in the cultures. In conclusion, our data show that IFNy blocks the development of macrophage-derived foam cells by inhibiting expression of ScR. This suggests that macrophage-T lymphocyte interactions may reduce intracellular cholesterol accumulation in the atherosclerotic plaque. (J. Clin. Invest. 1992. 89:1322-1330.)