Activation of inflammatory mediators and potential role of ah-receptor ligands in foam cell formation.
Epidemiological data and in vivo animal experiments have indicated that exposure to the Ah-receptor (AhR) ligand dioxin and other dioxin-like compounds can lead to cardiovascular toxicity and atherosclerosis. Here, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand, on the differentiation of U937 cells into foam cells, which are considered to be early lesions of atherosclerosis. Our findings show that, like oxidized low-density lipoprotein (oxLDL), TCDD promotes the differentiation of U937 macrophages to atherogenic foam cells, verified by lipid accumulation and extensive formation of blebs on the cell surface, which are characteristics of foam cells. Through screening expression patterns of typical genes involved in atherosclerosis and foam cell generation, we could demonstrate that mRNA levels of cyclooxygenase-2, interleukin 1beta, and tumor necrosis factor-alpha were increased in a time- and dose-dependent manner in U937 macrophages treated with TCDD, like oxLDL, and that these changes accompanied significantly elevated levels of matrix-degrading metalloproteinases (MMP)-1, MMP-3, MMP-12, and MMP-13. Increased levels of MMPs were associated with TCDD-stimulated cell migration of U937 macrophages. These findings clearly indicate that AhR ligands, like TCDD, stimulate differentiation of U937 macrophages into potentially plaque-forming foam cells.
Vogel
Christoph F A
CF
Department of Environmental Toxicology and Center for Environmental Health Sciences, University of California, Davis, CA 95616, USA.
Sciullo
Eric
E
Matsumura
Fumio
F
D001161:Arteriosclerosis / Q000209:etiology; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008077:Lipoproteins, LDL / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism*
D004338:Drug Combinations; D018836:Inflammation Mediators; D007375:Interleukin-1; D008024:Ligands; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases