Oxidized low density lipoprotein suppresses the expression of tumor necrosis factor-alpha mRNA in stimulated murine peritoneal macrophages.
In the present report we have examined expression of the gene encoding the inflammatory monokine TNF-alpha in murine peritoneal macrophages treated with different forms of low density lipoprotein (LDL). LDL modified by oxidation in vitro is unable to stimulate inflammatory gene expression in peritoneal macrophages. However, treatment of macrophage cultures with oxidized LDL for 6 h or more resulted in a concentration and time-dependent suppression of TNF-alpha mRNA expression induced in response to stimulation with either LPS or maleylated BSA. This suppression was maximal after 12 h of exposure to oxidized LDL and at a concentration of 100 to 200 micrograms LDL cholesterol/ml of culture medium. The suppressive effect was restricted to oxidatively modified LDL as treatment with native LDL or acetylated LDL did not affect TNF-alpha mRNA expression, despite the fact that both acetylated and oxidized LDL lead to intracellular lipid accumulation. The expression of maleyl albumin-stimulated TNF-alpha mRNA expression could be reproduced by lipid extracts of oxidized LDL provided to macrophages at the same cholesterol concentration as from the intact lipoprotein particle. Extracts from native LDL were ineffective. These results suggest that oxidized lipid accumulation in monocytes infiltrating the arterial wall may lead to the suppression of certain inflammatory functions which, in turn, may influence the development of mature atherosclerotic lesions.
Hamilton
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Research Institute, Cleveland Clinic Foundation, OH 44195.
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Chisolm
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D000107:Acetylation; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol