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Activation of inflammatory mediators and potential role of Ah-receptor ligands in foam cell formation

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Abstract

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 1 β, and tumor necrosis factor-α 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.

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References

  1. Hay, A. and Tarrel, J. (1997). Mortality of power workers exposed to phenoxy herbicides and polychlorinated biphenyls in waste transformer oil. Ann. NY Acad. Sci. 837: 138–156.

    PubMed  CAS  Google Scholar 

  2. Bertazzi, P.A., Bernucci, I., Brambilla, G., Consonni, D., and Pesatori, A.C. (1998). The Seveso studies on early and long-term effects of dioxin exposure: a review. Environ. Health Perspect. 106:625–633.

    Article  PubMed  CAS  Google Scholar 

  3. Tokunaga, S., Hirota, Y., and Kataoka, K. (1999). Association between the result of blood test and blood PCB levels of chronic Yusho patients twenty five years after the outbreak. Fukuoka Igaku Zasshi 90:157–161.

    PubMed  CAS  Google Scholar 

  4. Flesch-Janys, D., Berg, J., Gurn, P., Manz, A., Nagels, S., Waltsgott, H., et al. (1995). Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from an herbicide production in Hamberg. Am. J. Epidemiol. 142:1165–1175.

    PubMed  CAS  Google Scholar 

  5. Swift, L.L., Gasiewicz, T.A., Dann, G.D., Soule, P.D., and Nel, R.A. (1981). Characterization of hyperlipidemia in guinea pigs induced by 2, 3, 7, 8-tetrach lorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 59:489–499.

    Article  PubMed  CAS  Google Scholar 

  6. Dalton, T.P., Kerzee, J.K., Wang, B., Miller, M., Dieter, M.Z., Lorenz, J.N., et al. (2001). Dioxin exposure is an environmental risk factor for ischemic heart disease. Cardiovasc. Toxicol. 1:285–298.

    Article  PubMed  CAS  Google Scholar 

  7. Brewster, D.W. (1985). Biochemical manifestations of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat guinea pig, hamster, rabbit, and mouse. Ph.D. thesis. Center for Environmental Toxicology and Department of Entomology, Michigan State University. East Lansing, MI.

    Google Scholar 

  8. Brewster, D.W. and Matsumura, F. (1988). Reduction of adipose tissue lipoprotein lipase activity as a result of in vivo administration of 3, 7, 8-tetrachlorodibenzo-p-dioxin to the guinea pig. Biochem. Pharmacol. 37:2247–2253.

    Article  PubMed  CAS  Google Scholar 

  9. Buja, L.M., Kita, T., Goldstein, J.L., Watanabe, Y., and Brown, M.S. (1983). Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia. Arteriosclerosis 3:87–101.

    PubMed  CAS  Google Scholar 

  10. Komura, K., Hayashi, S., Makino, I., Poellinger, L., and Tanaka, H. (2001). Arylhydrocarbon receptor/dioxin receptor in human monocytes and macrophages. Mol. Cell. Biochem. 226:107–118.

    Article  PubMed  CAS  Google Scholar 

  11. Martens, J.S., Reiner, N.E., Herrera-Velit, P., and Steinbrecher, U.P. (1998). Phosphatidylinositol 3-kinase is involved in the induction of macrophage growth by oxidized low density lipoprotein. J. Biol. Chem. 9:4915–4920.

    Article  Google Scholar 

  12. Kasturi, R. and Joshi, V.C. (1982). Hormonal regulation of stearoyl coenzyme A desaturase activity and lipogenesis during adipose conversion of 3T3-L1 cells. J. Biol. Chem. 257:12224–12230.

    PubMed  CAS  Google Scholar 

  13. Vogel, C.F., Sciullo, E., Park, S., Liedtke, C., Trautwein, C., and Matsumura, F. (2004). Dioxin increases C/EBPβ transcription by activating cAMP/PKA. J. Biol. Chem. 279: 8886–8894.

    Article  PubMed  CAS  Google Scholar 

  14. Rosen, S. and Skaletsky, H.J. (2000). Primer3 on the WWW for general users and for biologist programmers, in Bioinformatics Methods and Protocols: Methods in Molecular Biology (Krawetz, S. and Misener, S., eds.), Humana Press, Totowa, NJ, pp. 365–386.

    Google Scholar 

  15. Jones, N.L., Allen, N.S., Willingham, M.C., and Lewis, J.C. (1999). Modified LDLs induce and bind to membrane ruffles on macrophages. Anat. Rec. 255:44–56.

    Article  PubMed  CAS  Google Scholar 

  16. Moore, K.J., Fabunmi, R.P., Andersson, L.P., and Freeman, M.W. (1998). In vitro-differentiated embryonic stem cell macrophages: a model system for studying atherosclerosis-associated macrophage functions. Arterioscler. Thromb. Vasc. Biol. 18:1647–1654.

    PubMed  CAS  Google Scholar 

  17. Burgess, J.W., Kiss, R.S., Zheng, H., Zachariah, S., and Marcel, Y.L. (2002). Trypsin-sensitive and lipid-containing sites of the macrophage extracellular matrix bind apolipoprotein A-I and participate in ABCA1-dependent cholesterol efflux. J. Biol. Chem. 277:31318–31326.

    Article  PubMed  CAS  Google Scholar 

  18. Hosoi, T., Takeda, K., and Konno, K. (1989). Synergism of prostaglandin E2 plus TNF in induction of differentiation of human monocytoid leukemic U-937 cells. Anticancer Res. 9:615–618.

    PubMed  CAS  Google Scholar 

  19. Bamba, H., Ota, S., Kato, A., Kawamoto, C., and Fujiwara, K. (2000). Prostaglandins up-regulate vascular endothelial growth factor production through distinct pathways in differentiated U937 cells. Biochem. Biophys. Res. Commun. 273:485–491.

    Article  PubMed  CAS  Google Scholar 

  20. Chisolm, G.M.I. and Chai, Y. (2000). Regulation of cell growth by oxidized LDL. Free Radic. Biol. Med. 28: 1697–1707.

    Article  PubMed  CAS  Google Scholar 

  21. Charles, G.D. and Shiverick, K.T. (1997). 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases mRNA levels for interleukin-1 beta, urokinase plasminogen activator, and tumor necrosis factor-alpha in human uterine endometrial adenocarcinoma RL95-2 cells. Biochem. Biophys. Res. Commun. 238:338–342.

    Article  PubMed  CAS  Google Scholar 

  22. Rier, S.E., Coe, C.L., Lemieux, A.M., Martin, D.C., Morris, R., Lucier, G., et al. (2001). Increased tumor necrosis factor-alpha production by peripheral blood leukocytes from TCDD-exposed rhesus monkeys. Toxicol. Sci. 60:327–337.

    Article  PubMed  CAS  Google Scholar 

  23. Sutter, T.R., Guzman, K., Dold, K.M., and Greenlee, W.F. (1991). Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta. Science 254: 415–418.

    Article  PubMed  CAS  Google Scholar 

  24. Clark, G., Taylor, M.J., Tritscher, A.M., and Lucier, G.W. (1991). Tumor necrosis factor involvement in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated endotoxin hypersensitivity in C57BL/6J mice congenic at the Ah locus. Toxicol. Appl. Pharmacol. 111:422–431.

    Article  PubMed  CAS  Google Scholar 

  25. Kerkvliet, N.I. (2002). Recent advances in understanding the mechanisms of TCDD immunotoxicity. Int. Immunopharmacol. 2:277–291.

    Article  PubMed  CAS  Google Scholar 

  26. Kerkvliet, N.I. and Oughton, J.A. (1993). Acute inflammatory response to sheep red blood cell challenge in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): phenotypic and functional analysis of peritoneal exudate cells. Toxicol. Appl. Pharmacol. 119:248–257.

    Article  PubMed  CAS  Google Scholar 

  27. Matsumura, F. (2003). On the significance of the role of cellular stress response reactions in the toxic actions of dioxin. Biochem. Pharmacol. 66:527–540.

    Article  PubMed  CAS  Google Scholar 

  28. Lee, W.H., Kim, S.H., Lee, Y., Lee, B.B., Kwon, B., Song, H., et al. (2001). Tumor necrosis factor receptor superfamily 14 is involved in atherogenesis by inducing proinflammatory cytokines and matrix metalloproteinase. Arterioscler. Thromb. Vasc. Biol. 21:2004–2010.

    PubMed  CAS  Google Scholar 

  29. Borden, P. and Heller, R.A. (1997). Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix matalloproteinases. Crit. Rev. Eukaryot. Gene Expr. 7:159–178.

    PubMed  CAS  Google Scholar 

  30. Herschman, H. (1996). Prostaglandin synthase 2. Biochem. Biophys. Acta 1299:125–140.

    PubMed  Google Scholar 

  31. Baker, C., Roger, J.C.H., Evans, T.J., Pomerance, A., Maclouf, J., Creminon, C., et al. (1999). Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler. Thromb. Vasc. Biol. 19:646–655.

    PubMed  CAS  Google Scholar 

  32. Schonbeck, U., Sukhova, G.K., Graber, P., Coulter, S., and Libby, P. (1999). Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am. J. Pathology 155:1281–1291.

    CAS  Google Scholar 

  33. Vogel, C., Schuhmacher, U.S., Degen, G.H., Goebel, C., and Abel, J. (1997). Differential effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of prostaglandin-H synthase isoenzymes in mouse tissues. Adv. Exp. Med. Biol. 433:139–143.

    PubMed  CAS  Google Scholar 

  34. Feng, Y., Schreiner, G.F., Chakravarty, S., Liu, D.Y., and Joly, A.H. (2001). Inhibition of the mitogen activated protein kinase, p38 alpha, prevents proinflammatory cytokine induction by human adherent mononuclear leukocytes in response to lipid loading. Atherosclerosis 158: 331–338.

    Article  PubMed  CAS  Google Scholar 

  35. Deigner, H.P. and Claus, R. (1996). Stimulation of mitogen activated protein kinase by LDL and oxLDL in human U-937 macrophage-like cells. FEBS Lett. 385: 149–153.

    Article  PubMed  CAS  Google Scholar 

  36. Vogel, C. and Matsumura, F. (2003). Interaction of 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induced cell differentiation in mouse embryonic fibroblasts (MEF) involves tyrosine kinase c-src. Biochem. Pharmacol. 66: 1231–1244.

    Article  PubMed  CAS  Google Scholar 

  37. Shertzer, H.G., Puga, A., Chang, C., Smith, P., Nebert, D.W., Setchell, K.D., et al. (1999). Inhibition of CYP1A1 enzyme activity in mouse hepatoma cell culture by soybean isoflavones. Chem. Biol. Intract. 123:31–49.

    Article  CAS  Google Scholar 

  38. Tan, Z., Chang, X., Puga, A., and Xia, Y. (2002). Activation of mitogen-activated protein kinases (MAPKs) by aromatic hydrocarbons: role in the regulation of aryl hydrocarbon receptor (AhR) function. Biochem. Pharmacol. 64: 771–780.

    Article  PubMed  CAS  Google Scholar 

  39. Tannheimer, S.L., Ethier, S.P., Caldwell, K.K., and Burchiel, S.W. (1998). Benzo(a)pyrene- and TCDD-induced alterations in tyrosine phosphorylation and insulin-like growth factor signaling pathways in the MCF-10A human mammary epithelial cell line. Carcinogenesis 19: 1291–1297.

    Article  PubMed  CAS  Google Scholar 

  40. Ponstler, A.V., St. Hilaire, A., Marathe, G.K., Zimmerman, G.A., and McIntyre, T.M. (2002). Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein. J. Biol. Chem. 277:13029–13036.

    Article  Google Scholar 

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Correspondence to Fumio Matsumura.

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Vogel, C.F.A., Sciullo, E. & Matsumura, F. Activation of inflammatory mediators and potential role of Ah-receptor ligands in foam cell formation. Cardiovasc Toxicol 4, 363–373 (2004). https://doi.org/10.1385/CT:4:4:363

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