Abstract
Regulation of expression of the scavenger receptor is thought to play a critical role in the accumulation of lipid by macrophages in atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha) has been shown to suppress macrophage scavenger receptor function (van Lenten, B.J., and Fogelman, A.M. (1992) J. Immunol. 148, 112-6). However, the mechanism by which it does so is unknown. We evaluated the mechanism by which TNF-alpha inhibited macrophage scavenger receptor surface expression and binding of acetylated low density lipoprotein (aLDL). Binding of aLDL to phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages was suppressed by TNF-alpha in a dose-dependent manner. Inhibition of aLDL binding was paralleled by a reduction of macrophage scavenger receptor protein as detected by the Western blot. TNF-alpha partially decreased macrophage scavenger receptor mRNA steady state levels in PMA-differentiated THP-1 macrophages, a result that was confirmed by reverse transcription-polymerase chain reaction. PMA increased the luciferase activity driven by the macrophage scavenger receptor promoter in the transfected cells, whereas TNF-alpha partially reduced luciferase activity. However, macrophage scavenger receptor mRNA half-life was dramatically reduced in cells treated with TNF-alpha relative to untreated cells. Reduction in macrophage scavenger receptor message in response to TNF-alpha was dependent on new protein synthesis because it was blocked by cycloheximide. These results indicate that TNF-alpha regulates macrophage scavenger receptor expression in PMA-differentiated THP-1 macrophages by transcriptional and post-transcriptional mechanisms but principally by destabilization of macrophage scavenger receptor mRNA.
Highlights
Macrophage scavenger receptors bind oxidized low density lipoprotein (LDL)1 and acetylated LDL, as well as other
phorbol 12-myristate 13-acetate (PMA) and macrophage colony-stimulating factor (M-CSF) equivalently increased the specific binding (4 °C) of 125I-acetylated LDL (aLDL) to THP-1 macrophages compared with untreated THP-1 monocytes (Fig. 1A)
The Bmax of undifferentiated THP-1 monocytes, PMA-differentiated THP-1 macrophages treated with TNF-␣ (PMA ϩ TNF-␣), as well as THP-1 monocytes treated with TNF-␣ and M-CSFdifferentiated THP-1 macrophages treated with TNF-␣, were equivalent
Summary
Macrophage scavenger receptors bind oxidized low density lipoprotein (LDL)1 and acetylated LDL (aLDL), as well as other. We demonstrate that TNF-␣ inhibits macrophage scavenger receptor binding activity, surface protein expression, and mRNA levels, with subsequent down-regulation of macrophage scavenger receptor-mediated ACAT activity and cholesterol esterification in PMA-differentiated THP-1 macrophages. Macrophage scavenger receptor mRNA was not detected in undifferentiated THP-1 monocytes (not treated with PMA), and TNF-␣ had no effect on this baseline expression.
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