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Effect of ziram on natural killer, lymphokine-activated killer, and cytotoxic T lymphocyte activity

  • Organ Toxicity and Mechanisms
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Abstract

Ziram is a carbamate pesticide, which is widely used throughout the world as a fungicide in agriculture and as an accelerating agent in latex production. In the present study, we investigated the effect of ziram at 0.031–4 μM in vitro on human natural killer (NK) and lymphokine-activated killer (LAK) and murine cytotoxic T lymphocyte (CTL) activity and found that it significantly inhibited all three activities in a concentration-dependent manner. To explore the mechanism of ziram-induced inhibition of NK activity, NK-92MI cells, a human NK cell line, were used. We previously confirmed that NK-92MI cells express CD56, perforin, granzyme (Gr) A, GrB, Gr3/K, and granulysin and are highly cytotoxic to K562 cells in the chromium release assay. NK-92MI cells were treated with ziram at 0.125–4 μM for 4 or 16 h at 37°C in vitro. Then, intracellular levels of perforin, GrA, GrB, Gr3/K, and granulysin were determined by flow cytometry. It was found that ziram significantly reduced Gr3/K, granulysin, perforin, GrA, and GrB levels. The extent of the decrease differed among the proteins, and the order was as follows: Gr3/K > granulysin > perforin, GrA, and GrB. Taken together, these findings suggest the ziram-induced inhibition of NK, LAK, and CTL activities to be at least partially mediated by decreases in the intracellular levels of Gr3/K, granulysin, perforin, GrA, and GrB.

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References

  • Beresford PJ, Kam CM, Powers JC, Lieberman J (1997) Recombinant human granzyme A binds to two putative HLA-associated proteins and cleaves one of them. Proc Natl Acad Sci USA 94:9285–9290

    Article  PubMed  CAS  Google Scholar 

  • Clayberger C, Krensky AM (2003) Granulysin. Curr Opin Immunol 15:560–565

    Article  PubMed  CAS  Google Scholar 

  • Hirata Y, Inagaki H, Shimizu T, Li Q, Nagahara N, Minami M, Kawada T (2006) Expression of enzymatically active human granzyme 3 in Escherichia coli for analysis of its substrate specificity. Arch Biochem Biophys 446:35–43

    Article  PubMed  CAS  Google Scholar 

  • Kägi D, Vignaux F, Ledermann B, Bürki K, Depraetere V, Nagata S, Hengartner H, Golstein P (1994a) Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265:528–530

    Article  PubMed  Google Scholar 

  • Kägi D, Ledermann B, Bürki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H (1994b) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37

    Article  PubMed  Google Scholar 

  • Li Q, Kawada T (2006) The new mechanism of organophosphorus pesticides-induced inhibition of cytolytic activity of killer cells. Cell Mol Immunol 3:171–178

    PubMed  CAS  Google Scholar 

  • Li Q, Hirata Y, Piao S, Minami M (2000) The by-products generated during sarin synthesis in the Tokyo sarin disaster induced inhibition of natural killer and cytotoxic T lymphocyte activity. Toxicology 146:209–220

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Nagahara N, Takahashi H, Takeda K, Okumura K, Minami M (2002) Organophosphorus pesticides markedly inhibit the activities of natural killer, cytotoxic T lymphocyte and lymphokine-activated killer: a proposed inhibiting mechanism via granzyme inhibition. Toxicology 172:181–190

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Nakadai A, Takeda K, Kawada T (2004) Dimethyl 2, 2-dichlorovinyl phosphate (DDVP) markedly inhibits activities of natural killer cells, cytotoxic T lymphocytes and lymphokine-activated killer cells via the Fas-ligand/Fas pathway in perforin-knockout (PKO) mice. Toxicology 204:41–50

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Nakadai A, Ishizaki M, Morimoto K, Ueda A, Krensky AM, Kawada T (2005) Dimethyl 2, 2-dichlorovinyl phosphate (DDVP) markedly decreases the expression of perforin, granzyme A and granulysin in human NK-92CI cell line. Toxicology 213:107–116

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Nakadai A, Matsushima H, Miyazaki Y, Krensky AM, Kawada T, Morimoto K (2006) Phytoncides (wood essential oils) induce human natural killer cell activity. Immunopharmacol Immunotoxicol 28:319–333

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Kobayashi M, Kawada T (2007) Organophosphorus pesticides induce apoptosis in human NK cells. Toxicology 239:89–95

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Kobayashi M, Kawada T (2008) DDVP markedly decreases the expression of granzyme B and granzyme 3/K in human NK cells. Toxicology 243:294–302

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Kobayashi M, Kawada T (2011) Ziram induces apoptosis and necrosis in human immune cells. Arch Toxicol 85:355–361

    Article  PubMed  CAS  Google Scholar 

  • MacDonald G, Shi L, Vande Velde C, Lieberman J, Greenberg AH (1999) Mitochondria-dependent and -independent regulation of granyzme B-induced apoptosis. J Exp Med 189:131–143

    Article  PubMed  CAS  Google Scholar 

  • Ogawa K, Takamori Y, Suzuki K, Nagasawa M, Takano S, Kasahara Y, Nakamura Y, Kondo S, Sugamura K, Nakamura M, Nagata K (2003) Granulysin in human serum as a marker of cell-mediated immunity. Eur J Immunol 33:1925–1933

    Article  PubMed  CAS  Google Scholar 

  • Okada S, Li Q, Whitin JC, Clayberger C, Krensky AM (2003) Intracellular mediators of granulysin-induced cell death. J Immunol 171:2556–2562

    PubMed  CAS  Google Scholar 

  • Richardson ML (1993) Z19: ziram. In: Richardson ML (ed) The dictionary of substances and their effects, vol 7. The Royal Society of Chemistry, Cambridge, pp 908–911

    Google Scholar 

  • Shi L, Kam CM, Powers JC, Aebersold R, Greenberg AH (1992) Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions. J Exp Med 176:1521–1529

    Article  PubMed  CAS  Google Scholar 

  • Smyth MJ, Trapani JA (1995) Granzymes: exogenous proteinases that induce target cell apoptosis. Immunol Today 16:202–206

    Article  PubMed  CAS  Google Scholar 

  • Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG (1999) Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther 10:1359–1373

    Article  PubMed  CAS  Google Scholar 

  • Taylor TR, Whalen MM (2009) Effects of ziram on tumor-cell-binding capacity, cell-surface marker expression, and ATP levels of human natural killer cells. Cell Biol Toxicol 25:447–455

    Article  PubMed  CAS  Google Scholar 

  • Taylor TR, Tucker T, Whalen MM (2005) Persistent inhibition of human natural killer cell function by ziram and pentachlorophenol. Environ Toxicol 20:418–424

    Article  PubMed  CAS  Google Scholar 

  • Whalen MM, Loganathan BG, Yamashita N, Saito T (2003) Immunomodulation of human natural killer cell cytotoxic function by triazine and carbamate pesticides. Chem Biol Interact 145:311–319

    Article  PubMed  CAS  Google Scholar 

  • Wilson S, Dzon L, Reed A, Pruitt M, Whalen MM (2004) Effects of in vitro exposure to low levels of organotin and carbamate pesticides on human natural killer cell cytotoxic function. Environ Toxicol 19:554–563

    Article  PubMed  CAS  Google Scholar 

  • Zhang D, Beresford PJ, Greenberg AH, Lieberman J (2001) Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proc Natl Acad Sci USA 98:5746–5751

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology. We are grateful to the staff at the Department of Hygiene and Public Health, Nippon Medical School for their assistance.

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Authors and Affiliations

  1. Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan

    Qing Li, Maiko Kobayashi & Tomoyuki Kawada

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  1. Qing Li
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  2. Maiko Kobayashi
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  3. Tomoyuki Kawada
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Correspondence to Qing Li.

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Li, Q., Kobayashi, M. & Kawada, T. Effect of ziram on natural killer, lymphokine-activated killer, and cytotoxic T lymphocyte activity. Arch Toxicol 86, 475–481 (2012). https://doi.org/10.1007/s00204-011-0771-5

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  • DOI: https://doi.org/10.1007/s00204-011-0771-5

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