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Effects of lipoxygenase and cycloxygenase inhibitors on murine antibody-dependent cellular cytotoxicity (ADCC)

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Research in Experimental Medicine

Summary

The purpose of this study was to determine the effects that specific inhibition of arachidonic acid (AA) metabolism has on the antibody-dependent cellular cytotoxicity (ADCC) of murine spleen cells. The action of three inhibitors of the lipoxygenase (LO) pathway—nordihydroguaiaretic acid (NDGA), esculetin (Es), and phenantroline (Phe)—was compared with that of three inhibitors of the cycloxygenase (CO) pathway—indomethacin (INDO), acetyl salicylic acid (ASA), and imidazole (IMI). All the LO inhibitors suppressed ADCC function in a dose-dependent manner, but NDGA was the most potent inhibitor of this cytolytic activity. In fact, NDGA inhibited the ADCC function with 97% inhibition at 10μM, while Phe and Es, at the same concentration, inhibited ADCC by 21% and 19%, respectively. However, CO inhibitors did not markedly affect ADCC function and only some doses of them had a slight, but significant, depressing effect (8–11% inhibition at 0.01–0.1 μM of INDO, 7% inhibition at 400μM of ASA, and 13% inhibition at 800–1000μM of IMI). These results suggest the LO pathway of the arachidonic acid metabolism plays an important role in regulating ADCC activity of murine spleen cells and the products of the CO pathway have little effect on ADCC lysis.

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References

  1. Blomgren H, Hammarstöm S, Wasserman J (1988) Synergistic enhancement of mitogen responses of human lymphocytes by inhibitors of cyclo-oxygenase and lipoxygenase. Int Arch Allergy Appl Immunol 86:62–68

    PubMed  CAS  Google Scholar 

  2. Borgeat P, Naccache PH (1990) Biosynthesis and biological activity of leukotriene B4. Clin Biochem 23:459–468

    Article  PubMed  CAS  Google Scholar 

  3. Bray RB, Brahmi Z (1986) Role of lipoxygenation in human natural killer cell activation. J Immunol 136:1783–1790

    PubMed  CAS  Google Scholar 

  4. Cohen N, Weber G, Banner BL Welton AF, Hope WC, Crowley H, Anderson WA, Simko BA, O'Donell M, Coffey JW, Fiedler-Nagy C, Batula-Bernardo C (1984) Analogs of arachidonic acid methylated at C-7 and C-10 as inhibitors of leukotriene biosynthesis. Prostaglandins 27:553–562

    Article  PubMed  CAS  Google Scholar 

  5. Davies P (1987–88) Lipoxygenase products in immunity. Immunol Invest 16:623–647

    PubMed  CAS  Google Scholar 

  6. Denizot F, Lang R (1986) Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol 89:271–277

    Article  CAS  Google Scholar 

  7. Elliott GR, Tak C, Pellens C, Ben-Efraim S, Bonta IL (1988) Indomethacin stimulation of macrophage cytostasis against MOPC-315 tumor cells is inhibited by both prostaglandin E2 and nordihydroguaiaretic acid. a lipoxygenase inhibitor. Cancer Immunol Immunother 27:133–136

    Article  PubMed  CAS  Google Scholar 

  8. Feuerstein G, Hallenbeck JM (1987) Leukotrienes in health and disease. FASEB J 1:186–192

    PubMed  CAS  Google Scholar 

  9. Gagnon L, Filion LG, Dubois C, Rola-Pleszczynski M (1989) Leukotrienes and macrophage activation: augmented cytotoxic activity and enhanced interleukin 1, tumor necrosis factor and hydrogen peroxide production. Agents Actions 26:141–147

    Article  PubMed  CAS  Google Scholar 

  10. Giordano M, Geffner JR, Serebrinski GP, Palermo MS, Isturiz MA (1988) Different requirements for the induction of antibody-dependent and immune complexes triggered cytotoxicity mediated by monocytes. Immunol Lett 17:109–114

    Article  PubMed  CAS  Google Scholar 

  11. Granström E (1981) Metabolism of prostaglandins and thromboxanes. In: Berti F, Velo GP (eds) The prostaglandin system: endoperoxides, prostacyclin and thromboxanes. Plenum Press, New York London, pp 39–48

    Google Scholar 

  12. Graziano FR, Fanger MW (1987) FcγRI and FcγRII on monocytes and granulocytes are cytotoxic trigger molecules for tumor cells. J Immunol 139:3536–3541

    PubMed  CAS  Google Scholar 

  13. Gryglewski RJ (1981) Pharmacological interference in arachidonic acid cascade. In: Berti F, Velo GP (eds) The prostaglandin system: endoperoxides, prostacyclin and thromboxanes. Plenum Press, New York London, pp 85–96

    Google Scholar 

  14. Hamasaki Y, Tai HH (1985) Gossypol, a potent inhibitor of arachidonate 5- and 12-lipoxygenases. Biochim Biophys Acta 834:37–41

    PubMed  CAS  Google Scholar 

  15. Hattori T, Hirata F, Hoffman T, Hizuta A, Herberman RB (1983) Inhibition of human natural killer (NK) activity and antibody dependent cellular cytotoxicity (ADCC) by lipomodulin, a phospholipase inhibitory protein. J Immunol 131:662–665

    PubMed  CAS  Google Scholar 

  16. Hoffman T, Hirata F, Bougnoux P, Fraser BA, Goldfarb RH, Herberman RB, Axelrod J (1981) Phospholipid methylation and phospholipase A2 activation in cytotoxicity by human natural killer cells. Proc Natl Acad Sci USA 78:3839–3843

    Article  PubMed  CAS  Google Scholar 

  17. Jondal M, Kullman C, Lindgren JA, Rossi P (1985) The lipoxygenase pathway in the human NK cell system. In: Henkart P, Martz E (eds) Mechanisms of cell-mediated cytotoxicity II. Plenum Press, New York, pp 257–270

    Google Scholar 

  18. Kelly JP, Johnson MC, Parker CW (1979) Effect of inhibitors of arachidonic acid metabolism on mitogenesis in human lymphocytes: possible role of thromboxanes and products of the lipoxygenase pathway. J Immunol 122:1563–1571

    PubMed  CAS  Google Scholar 

  19. Koren HS, Anderson SJ, Fisher DG, Copeland CS, Jensen PJ (1981) Regulation of human natural killing. I. The role of monocytes, interferon, and prostaglandins. J Immunol 127:2007–2013

    PubMed  CAS  Google Scholar 

  20. Kuhn C, Bekemeier H, Hirschelmann R, Gliessler AJ (1988) Action of cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitors as well as of oxygen free radical scavengers (OFRS) in the inflammation-induced vasodepression. Biomed Biochim. Acta 47:S320-S323

    PubMed  CAS  Google Scholar 

  21. Leung KH, Ip MM (1986) Regulation of rat natural killing. II. Inhibition of cytolysis and activation by inhibitors of lipoxygenase: possible role of leukotrienes. Cell Immunol 100:474–484

    Article  PubMed  Google Scholar 

  22. Leung KH, Ip MM, Koren HS (1985) The role of the lipoxygenase in regulation of NK activity. In: Herberman RB, Callewaert DM (eds) Mechanisms of cytotoxicity by NK cells. Academic Press, New York, pp 253–261

    Google Scholar 

  23. Leung KH, Ip MM, Koren HS (1986) Regulation of human natural killing. IV. Role of lipoxygenase in regulation of natural activity. Scand J Immunol 24:371–380

    Article  PubMed  CAS  Google Scholar 

  24. Lewis RA, Austen KF, Soberman RJ (1990) Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 323:645–655

    Article  PubMed  CAS  Google Scholar 

  25. Moncada S, Vane JR (1979) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 30:293–331

    Google Scholar 

  26. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: applications to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  27. Nair MPN, Schwartz SA (1984) Immunomodulatory effects of corticosteroids on natural killer and antibody-dependent cellular cytotoxic activities of human lymphocytes. J Immunol 132:2876–2881

    PubMed  CAS  Google Scholar 

  28. Neichi T, Koshihara Y, Murota SI (1983) Inhibitory effect of esculetin of 5-lipoxygenase and leukotriene biosynthesis. Biochim Biophys Acta 753:130–132

    PubMed  CAS  Google Scholar 

  29. Ortaldo JR, Herberman RB (1984) Heterogeneity of natural killer cells. Annu Rev Immunol 2:359–394

    Article  PubMed  CAS  Google Scholar 

  30. Ortaldo JR, Mathieson BJ, Wiltrout RH (1988) Characterization and functions of natural killer cells. Ann Inst Pasteur Immunol 139:444–450

    Article  PubMed  CAS  Google Scholar 

  31. Parkar BA, McCormick ME, Foster SJ (1990) Leukotrienes do not regulate interleukin 1 production by activated macrophages. Biochem Biophys Res Commun 169:422–429

    Article  PubMed  CAS  Google Scholar 

  32. Pearson GR (1978) In vitro and in vivo investigations on antibody-dependent cellular cytotoxicity. Curr Top Microbiol Immunol 80:65–96

    PubMed  CAS  Google Scholar 

  33. Rola-Pleszczynski M, Gagnon L, Sirois P (1983) Leukotriene B4 augments human natural cytotoxicity cell activity. Biochem Biophys Res Commun 113:531–537

    Article  PubMed  CAS  Google Scholar 

  34. Samuelsson B, Dahlén SE, Lindgren JA, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237:1171–1175

    Article  PubMed  CAS  Google Scholar 

  35. Seaman WE (1983) Human natural killer cell activity is reversibly inhibited by antagonists of lipoxygenation. J Immunol 131:2953–2957

    PubMed  CAS  Google Scholar 

  36. Seaman WE, Woodcock J (1984) Human and murine natural killer cell activity may require lipoxygenation of arachidonic acid. J Allergy Clin Immunol 74:407–411

    Article  PubMed  CAS  Google Scholar 

  37. Suthanthiran M, Solomon SD, Williams PS, Rubin AL, Novogrodsky A, Stenzel KH (1984) Hydroxyl radical scavengers inhibit human natural killer cell activity. Nature 307: 276–278

    Article  PubMed  CAS  Google Scholar 

  38. Villa ML, Valenti F, Mantovani M (1988) Modulation of natural killing by cyclo-and lipooxygenase inhibitors. Immunology 63:93–97

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Unidad de Inmunologia Experimental, Centro de Investigación, Hospital La Fe, Avenida Campanar No. 21, E-46009, Valencia, Spain

    J. Hernández-Godoy, D. Planelles, A. Bayona, B. Balsalobre & A. González-Molina

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  1. J. Hernández-Godoy
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  2. D. Planelles
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  3. A. Bayona
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  4. B. Balsalobre
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  5. A. González-Molina
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Hernández-Godoy, J., Planelles, D., Bayona, A. et al. Effects of lipoxygenase and cycloxygenase inhibitors on murine antibody-dependent cellular cytotoxicity (ADCC). Res. Exp. Med. 192, 423–430 (1992). https://doi.org/10.1007/BF02576300

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  • DOI: https://doi.org/10.1007/BF02576300

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