Advertisement

Apoptosis

, Volume 10, Issue 2, pp 369–379 | Cite as

Zinc pyrithione induces apoptosis and increases expression of Bim

  • J. J. Mann
  • P. J. FrakerEmail author
Article

Abstract

We demonstrate herein that zinc pyrithione can induce apoptosis at nanomolar concentrations. Zinc pyrithione was a potent inducer of cell death causing greater than 40–60% apoptosis among murine thymocytes, murine splenic lymphocytes and human Ramos B and human Jurkat T cells. Conversely, the addition of a zinc chelator protected thymocytes against zinc pyrithione induced apoptosis indicating these responses were specific for zinc. Zinc-induced apoptosis was dependent on transcription and translation which suggested possible regulation by a proapoptotic protein. Indeed, zinc induced a 1.9 and 3.4 fold increase respectively in expression of the BimEL and BimL isoforms and also stimulated production of the most potent isoform, BimS. This increase in Bim isoform expression was dependent on transcription being blocked by treatment with actinomycin D. Overexpression of Bcl-2 or Bcl-xL provided substantial protection of Ramos B and Jurkat T cells against zinc-induced apoptosis. Zinc also activated the caspase cascade demonstrated by cleavage of caspase 9. Addition of specific inhibitors for caspase 9 and caspase 3 also blocked zinc-induced apoptosis. The data herein adds to the growing evidence that free or unbound zinc could be harmful to cells of the immune system.

Keywords

apoptosis Bcl-2 Bim caspases zinc pyrithione 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Walsh CT, Sandstead HH, Prasad AS, Newberne PM, Fraker PJ. Zinc: Health effects and research priorities for the 1990s. Environ Health Perspect 1994; 102(Suppl2): 5–46.PubMedGoogle Scholar
  2. 2.
    Dardenne M. Zinc and immune function. Eur J Clin Nutr 2002; 56(Suppl 3): S20–S23.PubMedGoogle Scholar
  3. 3.
    Telford WG, Fraker PJ. Preferential induction of apoptosis in mouse CD4+CD8+αβ TCRloCD3εlo thymocytes by zinc. J Cell Physiol 1995; 164: 259–270.PubMedGoogle Scholar
  4. 4.
    Walther UI, Wilhelm B, Walther S, Muckter H, Fichtl B. Zinc toxicity in various lung cell lines is mediated by glutathione and GSSG reductase activity. Biol Trace Elem Res 2000; 78: 163–177.PubMedGoogle Scholar
  5. 5.
    Feng P, Liang JY, Li TL, et al. Zinc induces mitochondria apoptogenesis in prostate cells. Mol Urol 2000; 4: 31–36.PubMedGoogle Scholar
  6. 6.
    Paramanantham R, Sit KH, Bay BH. Adding Zn2 + induces DNA fragmentation and cell condensation in cultured human Chang liver cells. Biol Trace Elem Res 1997; 58: 135–147.PubMedCrossRefGoogle Scholar
  7. 7.
    Suh SW, Chen JW, Motamedi M, et al. Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res 2000; 852: 268–273.PubMedGoogle Scholar
  8. 8.
    Suh SW, Thompson RB, Frederickson CJ. Loss of vesicular zinc and appearance of perikaryal zinc after seizures induced by pilocarpine. Neuroreport 2001; 12: 1523–1525.PubMedGoogle Scholar
  9. 9.
    Frederickson CJ, Bush AI. Synaptically released zinc: Physiological functions and pathological effects. Biometals 2001; 14: 353–366.PubMedGoogle Scholar
  10. 10.
    Frederickson CJ, Maret W, Cuajungco MP. Zinc and excitotoxic brain injury: A new model. Neuroscientist 2004; 10: 18–25.PubMedGoogle Scholar
  11. 11.
    Kozin SA, Zirah S, Rebuffat S, Hoa GH, Debey P. Zinc binding to Alzheimer’s Aβ 1–16) peptide results in stable soluble complex. Biochem Biophys Res Commun 2001; 285: 959–964.PubMedGoogle Scholar
  12. 12.
    Curtain CC, Ali F, Volitakis I, et al. Alzheimer’s disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 2001; 276: 20466–20473.PubMedGoogle Scholar
  13. 13.
    Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits β -amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 2001; 30: 665–676.PubMedGoogle Scholar
  14. 14.
    Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush AI. Metal chelation as a potential therapy for Alzheimer’s disease. Ann N Y Acad Sci 2000; 920: 292–304.PubMedCrossRefGoogle Scholar
  15. 15.
    Kim BJ, Kim YH, Kim S, et al. Zinc as a paracrine effector in pancreatic islet cell death. Diabetes 2000; 49: 367–372.PubMedGoogle Scholar
  16. 16.
    Maret W. Cellular zinc and redox states converge in the metallothionein/thionein pair. J Nutr 2003; 133: 1460S–1462S.PubMedGoogle Scholar
  17. 17.
    Korichneva I, Hoyos B, Chua R, Levi E, Hammerling U. Zinc release from protein kinase C as the common event during activation by lipid second messenger or reactive oxygen. J Biol Chem 2002; 277: 44327–44331.PubMedGoogle Scholar
  18. 18.
    Zalewski PD, Forbes IJ, Seamark RF, et al. Flux of intracellular labile zinc during apoptosis (gene-directed cell death) revealed by a specific chemical probe, Zinquin. Chem Biol 1994; 1: 153–161.PubMedGoogle Scholar
  19. 19.
    Newmeyer DD, Ferguson-Miller S. Mitochondria. Releasing power for life and unleashing the machineries of death. Cell 2003; 112: 481–490.PubMedGoogle Scholar
  20. 20.
    Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–1312.CrossRefPubMedGoogle Scholar
  21. 21.
    Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770–776.CrossRefPubMedGoogle Scholar
  22. 22.
    Chao DT, Korsmeyer SJ. BCL-2 family: Regulators of cell death. Annu Rev Immunol 1998; 16: 395–419.PubMedGoogle Scholar
  23. 23.
    Opferman JT, Korsmeyer SJ. Apoptosis in the development and maintenance of the immune system. Nat Immunol 2003; 4: 410–415.PubMedGoogle Scholar
  24. 24.
    Whitehouse RC, Prasad AS, Rabbani PI, Cossack ZT. Zinc in plasma, neutrophils, lymphocytes, and erythrocytes as determined by flameless atomic absorption spectrophotometry. Clin Chem 1982; 28: 475–480.PubMedGoogle Scholar
  25. 25.
    Rathmell JC, Thompson CB. The central effectors of cell death in the immune system. Annu Rev Immunol 1999; 17: 781–828.PubMedGoogle Scholar
  26. 26.
    Telford WG, King LE, Fraker PJ. Rapid quantitation of apoptosis in pure and heterogeneous cell populations using flow cytometry. J Immunol Methods 1994; 172: 1–16.PubMedGoogle Scholar
  27. 27.
    Garvy BA, Telford WG, King LE, Fraker PJ. Glucocorticoids and irradiation-induced apoptosis in normal murine bone marrow B-lineage lymphocytes as determined by flow cytometry. Immunology 1993; 79: 270–277.PubMedGoogle Scholar
  28. 28.
    Laakko T, King L, Fraker P. Versatility of merocyanine 540 for the flow cytometric detection of apoptosis in human and murine cells. J Immunol Methods 2002; 261: 129–139.PubMedGoogle Scholar
  29. 29.
    Fraker PJ, Telford WG. A reappraisal of the role of zinc in life and death decisions of cells. Proc Soc Exp Biol Med 1997; 215: 229–236.PubMedGoogle Scholar
  30. 30.
    Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Annu Rev Immunol 1992; 10: 267–293.CrossRefPubMedGoogle Scholar
  31. 31.
    Gratiot-Deans J, Ding L, Turka LA, Nunez G. Bcl-2 proto-oncogene expression during human T cell development. Evidence for biphasic regulation. J Immunol 1993; 151: 83–91.PubMedGoogle Scholar
  32. 32.
    Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD. The role of zinc in caspase activation and apoptotic cell death. Biometals 2001; 14: 315–330.PubMedGoogle Scholar
  33. 33.
    Bouillet P, Metcalf D, Huang DC, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.PubMedGoogle Scholar
  34. 34.
    Kumar S, Vaux DL. Apoptosis. A cinderella caspase takes center stage. Science 2002; 297: 1290–1291.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Cell and Molecular Biology ProgramMichigan State UniversityEast LansingUSA
  2. 2.Department of Biochemistry & Molecular BiologyMichigan State UniversityEast LansingUSA

Personalised recommendations