Cell and Tissue Research

, Volume 318, Issue 2, pp 325–333 | Cite as

Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions

  • Daniel Schlittenhardt
  • Andreas Schober
  • Jens Strelau
  • Gabriel A. Bonaterra
  • Walther Schmiedt
  • Klaus Unsicker
  • Jürgen Metz
  • Ralf Kinscherf
Regular Article

Abstract

Growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) is a new member of the transforming growth factor beta (TGF-β) superfamily, which has most recently been found in activated macrophages (MΦ). We have now investigated GDF-15/MIC-1 in human MΦ after exposure to oxidized low-density lipoproteins (oxLDL) related mediators in vitro and in arteriosclerotic carotid arteries. Using RT-PCR and Western blotting a pronounced induction of GDF-15/MIC-1 expression by oxLDL, C6-ceramide, tumor necrosis factor (TNFα) and hydrogen peroxide (H2O2) was found in cultured human MΦ. In 11 human arteriosclerotic carotid arteries, immunohistochemical analyses supported by computer-assisted morphometry and regression analyses demonstrated a significant colocalization of GDF-15/MIC-1 immunoreactivity (IR) with oxLDL IR and manganese superoxide dismutase (MnSOD) IR in CD68 immunoreactive (ir) MΦ, which were also expressing AIF-IR (apoptosis-inducing factor), caspase-3-IR (CPP32), PARP-IR, c-Jun/AP-1-IR and p53-IR. Our data suggest that GDF-15/MIC-1 is inducible in human MΦ by oxLDL and its mediators in vitro and is supposed to contribute to oxidative stress dependent consequences in arteriosclerotic plaques, e.g. modulating apoptosis and inflammatory processes in activated MΦ.

Keywords

Apoptosis Arteriosclerosis Oxidative stress Oxidized low density lipoproteins TGF-β superfamily member Human 

Notes

Acknowledgements

The authors are grateful to Mrs. U. Traut for expert technical assistance.

References

  1. Albertoni M, Shaw PH, Nozaki M, Godard S, Tenan M, Hamou MF, Fairlie DW, Breit SN, Paralkar VM, de Tribolet N, Van Meir EG, Hegi ME (2002) Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. Oncogene 21:4212–4219CrossRefPubMedGoogle Scholar
  2. Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE (2001) Cyclooxygenase inhibitors regulate the expression of a TGF-β superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 59:901–908PubMedGoogle Scholar
  3. Bauskin AR, Zhang HP, Fairlie WD, He XY, Russell PK, Moore AG, Brown DA, Stanley KK, Breit SN (2000) The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1. EMBO J 19:2212–2220CrossRefPubMedGoogle Scholar
  4. Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G (1999) Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development. Circulation 99:2883–2891PubMedGoogle Scholar
  5. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci USA 94:11514–11519CrossRefPubMedGoogle Scholar
  6. Böttner M, Laaff M, Schechinger B, Rappold G, Unsicker K, Suter-Crazzolara C (1999a) Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1). Gene 237:105–111CrossRefPubMedGoogle Scholar
  7. Böttner M, Suter-Crazzolara C, Schober A, Unsicker K (1999b) Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res 297:103–110CrossRefPubMedGoogle Scholar
  8. Böttner M, Krieglstein K, Unsicker K (2000) The TGF-βs: structure signalling and roles in nervous system development and function. J Neurochem 75:2227–2240Google Scholar
  9. Brown DA, Breit SN, Buring J, Fairlie WD, Bauskin AR, Liu T, Ridker PM (2002) Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study. Lancet 59:2159–2163CrossRefGoogle Scholar
  10. Burger-Kentischer A, Goebel H, Seiler R, Fraedrich G, Schaefer HE, Dimmeler S, Kleemann R, Bernhagen J, Ihling C (2002) Expression of macrophage migration inhibitory factor in different stages of human atherosclerosis. Circulation 105:1561–1566CrossRefPubMedGoogle Scholar
  11. Colton CA, Snell-Callanan J, Chernyshev ON (1998) Ethanol induced changes in superoxide anion and nitric oxide in cultured microglia. Alcohol Clin Exp Res 22:710–716PubMedGoogle Scholar
  12. Corradin SB, Buchmuller-Rouiller Y, Smith J, Suardet L, Mauel J (1993) Transforming growth factor beta 1 regulation of macrophage activation depends on the triggering stimulus. J Leukoc Biol 54:423–429PubMedGoogle Scholar
  13. Czernichow S, Hercberg S (2001) Interventional studies concerning the role of antioxidant vitamins in cardiovascular diseases: a review. J Nutr Health Aging 5:188–195PubMedGoogle Scholar
  14. Das KC, Lewis-Molock Y, White CW (1995) Activation of NF-kappa B and elevation of MnSOD gene expression by thiol reducing agents in lung adenocarcinoma (A549) cells. Am J Physiol 269:L588–L602PubMedGoogle Scholar
  15. De la Fuente M, Victor VM (2001) Ascorbic acid and N-acetylcysteine improve in vitro the function of lymphocytes from mice with endotoxin-induced oxidative stress. Free Radic Res 35:73–84PubMedGoogle Scholar
  16. Deigner HP, Claus R, Bonaterra GA, Gehrke C, Bibak N, Blaess M, Cantz M, Metz J, Kinscherf R (2001) Ceramide induces aSMase expression: implications for oxLDL-induced apoptosis. FASEB J 15:807–814CrossRefPubMedGoogle Scholar
  17. Erren M, Reinecke H, Junker R, Fobker M, Schulte H, Schurek JO, Kropf J, Kerber S, Breithardt G, Assmann G, Cullen P (1999) Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries. Arterioscler Thromb Vasc Biol 19:2355–2363PubMedGoogle Scholar
  18. Fairlie WD, Moore AG, Bauskin AR, Russell PK, Zhang HP, Breit SN (1999) MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation. J Leukoc Biol 65:2–5PubMedGoogle Scholar
  19. Fairlie WD, Russell PK, Moore AG, Zhang HP, Brown PK, Breit SN (2001) Epitope mapping of the transforming growth factor-β superfamily protein, macropahage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities. Biochemistry 40:65–73CrossRefPubMedGoogle Scholar
  20. Grand RJ, Milner AE, Mustoe T, Johnson GD, Owen D, Grant ML, Gregory CD (1995) A novel protein expressed in mammalian cells undergoing apoptosis. Exp Cell Res 218:439–451CrossRefPubMedGoogle Scholar
  21. Hutter R, Valdiviezo C, Sauter BV, Savontaus M, Chereshnev I, Carrick FE, Bauriedel G, Lüderitz B, Fallon JT, Fuster V, Badimon JJ (2004) Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis. Circulation 109:2001–2008CrossRefPubMedGoogle Scholar
  22. Idziorek T, Estaquier J, De Bels F, Ameisen JC (1995) YOPRO-1 permits cytofluorometric analysis of programmed cell death (apoptosis) without interfering with cell viability. J Immunol Meth 185:249–258CrossRefPubMedGoogle Scholar
  23. Ihling C, Menzel G, Wellens E, Monting JS, Schaefer HE, Zeiher AM (1997) Topographical association between the cyclin-dependent kinases inhibitor P21, p53 accumulation, and cellular proliferation in human atherosclerotic tissue. Arterioscler Thromb Vasc Biol 17:2218–2224PubMedGoogle Scholar
  24. Ihling C, Haendeler J, Menzel G, Hess RD, Fraedrich G, Schaefer HE, Zeiher AM (1998) Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. J Pathol 185:303–312CrossRefPubMedGoogle Scholar
  25. Jovinge S, Ares MP, Kallin B, Nilsson J (1996) Human monocytes/macrophages release TNF-alpha in response to Ox-LDL. Arterioscler Thromb Vasc Biol 16:1573–1579PubMedGoogle Scholar
  26. Kannan K, Amariglio N, Rechavi G, Givol D (2000) Profile of gene expression regulated by induced p53: connection to the TGF-beta family. FEBS Lett 470:77–82CrossRefPubMedGoogle Scholar
  27. Kinscherf R, Claus R, Deigner HP, Nauen O, Gehrke C, Hermetter A, Russwurm S, Daniel V, Hack V, Metz J (1997a) Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin-ceramide pathway in human macrophages. FEBS Lett 405:55–59CrossRefPubMedGoogle Scholar
  28. Kinscherf R, Deigner HP, Usinger C, Pill J, Wagner M, Kamencic H, Hou D, Chen M, Schmiedt W, Schrader M, Kovacs G, Kato K, Metz J (1997b) Induction of manganese superoxide dismutase by oxidized-LDL—its relevance in atherosclerosis of humans and heritable hyperlipidemic rabbits. FASEB J 11:1317–1328PubMedGoogle Scholar
  29. Kinscherf R, Claus R, Wagner M, Gehrke C, Kamencic H, Hou D, Chen M, Nauen O, Schmiedt W, Kovacs G, Pill J, Metz J, Deigner HP (1998) Apoptosis caused by oxidized-LDL is manganese superoxide dismutase and p53-dependent. FASEB J 12:461–467PubMedGoogle Scholar
  30. Kinscherf R, Wagner M, Kamencic H, Bonaterra GA, Hou D, Schiele RA, Deigner HP, Metz J (1999) Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits. Atherosclerosis 144:33–39CrossRefPubMedGoogle Scholar
  31. Kockx MM, Herman AG (2000) Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res 45:736–746CrossRefPubMedGoogle Scholar
  32. Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161CrossRefPubMedGoogle Scholar
  33. Li PX, Wong J, Ayed A, Ngo D, Brade AM, Arrowsmith C, Austin RC, Klamut HJ (2000) Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J Biol Chem 275:20127–20135CrossRefPubMedGoogle Scholar
  34. Libby P, Geng YJ, Aikawa M, Schoenbeck U, Mach F, Clinton SK, Sukhova GK, Lee RT (1996) Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol 7:330–335PubMedGoogle Scholar
  35. Mallat Z, Ohan J, Leseche G, Tedgui A (1997) Colocalization of CPP-32 with apoptotic cells in human atherosclerotic plaques. Circulation 96:424–428PubMedGoogle Scholar
  36. Martinet W, Knaapen MW, De Meyer GR, Herman AG, Kockx MM (2002) Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation 106:927–932CrossRefPubMedGoogle Scholar
  37. Mikita T, Porter G, Lawn RM, Shiffman D (2001) Oxidized low density lipoprotein exposure alters the transcriptional response of macrophages to inflammatory stimulus. J Biol Chem 276:45729–45739CrossRefPubMedGoogle Scholar
  38. Reckless J, Rubin EM, Verstuyft JB, Metcalfe JC, Grainger DJ (2001) A common phenotype associated with atherogenesis in diverse mouse models of vascular lipid lesions. J Vasc Res 38:256–265CrossRefPubMedGoogle Scholar
  39. Schober A, Böttner M, Strelau J, Kinscherf R, Bonaterra GA, Barth M, Schilling L, Fairlie WD, Breit SN, Unsicker K (2001) Expression of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 439:32–45CrossRefPubMedGoogle Scholar
  40. Schuster N, Krieglstein K (2002) Mechanisms of TGF-β-mediated apoptosis. Cell Tissue Res 307:1–14CrossRefPubMedGoogle Scholar
  41. Strelau J, Böttner M, Lingor P, Suter-Crazzolara C, Galter D, Jaszai J, Sullivan A, Schober A, Krieglstein K, Unsicker K (2000) GDF-15/MIC-1 a novel member of the TGF-beta superfamily. J Neural Transm Suppl 60:273–276PubMedGoogle Scholar
  42. Subramaniam S, Strelau J, Unsicker K (2003) Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways. J Biol Chem 278:8904–8912CrossRefPubMedGoogle Scholar
  43. Tashiro H, Shimokawa H, Yamamoto K, Momohara M, Tada H, Takeshita A (1997) Altered plasma levels of cytokines in patients with ischemic heart disease. Coron Artery Dis 8:143–147PubMedGoogle Scholar
  44. Topper JN (2000) TGF-beta in the cardiovascular system: molecular mechanisms of a context-specific growth factor. Trends Cardiovasc Med 10:132–137CrossRefPubMedGoogle Scholar
  45. Unsicker K, Strelau J (2000) Functions of transforming growth factor-beta isoforms in the nervous system. Cues based on localization and experimental in vitro and in vivo evidence. Eur J Biochem 267:6972–6975CrossRefPubMedGoogle Scholar
  46. van Vlijmen BJ, Gerritsen G, Franken AL, Boesten LS, Kockx MM, Gijbels MJ, Vierboom MP, van Eck M, van De Water B, van Berkel TJ, Havekes LM (2001) Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice. Circ Res 88:780–786PubMedGoogle Scholar
  47. Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M (2000) Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20:61–69PubMedGoogle Scholar
  48. Wintergerst ES, Jelk J, Rahner C, Asmis R (2000) Apoptosis induced by oxidized low density lipoprotein in human monocyte-derived macrophages involves CD36 and activation of caspase-3. Eur J Biochem 267:6050–6059CrossRefPubMedGoogle Scholar
  49. Zhang W, Shokeen M, Li D, Mehta JL (2003) Identification of apoptosis-inducing factor in human coronary artery endothelial cells. Biochem Biophys Res Commun 301:147–151CrossRefPubMedGoogle Scholar
  50. Zhao Y, Xue Y, Oberley TD, Kiningham KK, Lin SM, Yen HC, Majima H, Hines J, St-Clair D (2001) Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res 61:6082–6088PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Daniel Schlittenhardt
    • 1
  • Andreas Schober
    • 1
  • Jens Strelau
    • 1
  • Gabriel A. Bonaterra
    • 1
  • Walther Schmiedt
    • 2
  • Klaus Unsicker
    • 1
  • Jürgen Metz
    • 1
  • Ralf Kinscherf
    • 1
  1. 1.Department of Anatomy and Cell Biology III and Interdisciplinary Center of Neurosciences (IZN)University of HeidelbergHeidelbergGermany
  2. 2.Department of Cardiothoracic and Vascular SurgeryMainzGermany

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