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

• Published in: The Journal of biological chemistry 1996-03, Vol.271 (13), p.7767-7773
• Main Authors: Hsu, Hsien-Yeh, Nicholson, Andrew C., Hajjar, David P.
• Format: Article
• Language: English
• Subjects: Blotting, Northern; Cell Differentiation; Cell Line; Cycloheximide - pharmacology; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; Humans; Kinetics; Lipoproteins, LDL - metabolism; Luciferases; Macrophages - drug effects; Macrophages - immunology; Membrane Proteins; Oleic Acid; Oleic Acids - metabolism; Polymerase Chain Reaction; Protein Biosynthesis - drug effects; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - biosynthesis; Receptors, LDL - drug effects; Receptors, LDL - metabolism; Receptors, Lipoprotein; Receptors, Scavenger; Recombinant Proteins - pharmacology; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Scavenger Receptors, Class B; Tetradecanoylphorbol Acetate - pharmacology; Transcription, Genetic - drug effects; Transfection; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.13.7767

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.