Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages.

Abstract

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

Macrophage heterogeneity and cholesterol homeostasis: Classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL

“…Reports using the human monocyte cell line THP-1 indicate that IFNγ and the transcription factor that it signals through, STAT1, are responsible for increased foam cell formation and CD36 expression [42,43]. By contrast, similar studies performed using primary human MDMs however are in agreement with our own [44][45][46]. Geng and Hansson, for example, found that IFNγ caused a reduction in acetylated LDL cellular association and cholesterol accumulation [44].…”

Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300

“…Expression of the SR-A gene is positively regulated by macrophage colony-stimulating factor (M-CSF; refs. 8 -10) and is inhibited by IFN-␥ (11).…”

Oxidized low‐density lipoprotein induces the production of superoxide by neutrophils

“…The mechanism of superoxide production by ox-LDL-treated cells is not yet known, but it differs from the mechanisms of superoxide production by the PMA-treated and opsonized zymosantreated cells which were not inhibited by cytochalasin B. It has become evident that the oxidative modification of LDL which occurs in vivo may play an important role in the early stages of atherogenic disease [2,26]. Although macrophages are unable to efficiently accumulate native LDL, it is believed that ox-LDL is able to recruit monocytes and induce lipid-laden macrophages, termed foam cells, in atherosclerotic lesions, but the in vivo mechanism of LDL oxidation remains unclear.…”

“…The oxidative modification of low-density lipoprotein (LDL has been implicated in the pathogenesis of atherosclerosis [1,2]. The oxidized LDL (ox-LDk) is rapidly taken up by macrophages through its scavenger receptors and leads to the formation of lipid-laden macrophages (or foam cells) in the early stages of atherosclerosis [2].…”

“…The oxidized LDL (ox-LDk) is rapidly taken up by macrophages through its scavenger receptors and leads to the formation of lipid-laden macrophages (or foam cells) in the early stages of atherosclerosis [2]. During the oxidation of LDL, the polyunsaturated fatty acids in the LDL lipids are, in part, converted to lipid hydroperoxides and then to some aldehydes, which can alter the protein moiety of LDL (or apolipoprotein B) [3,4].…”