Inhibition of Macrophage Scavenger Receptor Activity by Tumor Necrosis Factor- Is Transcriptionally and Post-transcriptionally Regulated (*)

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-α (TNF-α) has been shown to suppress macrophage scavenger receptor function (van Lenten, B. J., and Fogelman, A. M.(1992) J. Immunol. 148, 112-116). However, the mechanism by which it does so is unknown. We evaluated the mechanism by which TNF-α 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-α 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-α 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-α partially reduced luciferase activity. However, macrophage scavenger receptor mRNA half-life was dramatically reduced in cells treated with TNF-α relative to untreated cells. Reduction in macrophage scavenger receptor message in response to TNF-α was dependent on new protein synthesis because it was blocked by cycloheximide. These results indicate that TNF-α 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.

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