Skip to main content
SpringerLink
Log in

Indomethacin up-regulates the generation of lymphokine-activated killer-cell activity and antibody-dependent cellular cytotoxicity mediated by interleukin-2

  • Original articles
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Summary

Prostaglandins can inhibit the generation of lymphokine-activated killer (LAK) cells by interleukin-2 (IL-2) whereas indomethacin augmented the induction of LAK cells by inhibiting prostaglandin synthesis. In the present study we demonstrate that prostaglandin E2 substantially inhibited the generation of both LAK and antibody-dependent cellular cytotoxicity (ADCC) activity by IL-2. In addition, indomethacin enhanced the induction of LAK activity and ADCC in splenocytes exposed to IL-2 in vitro. The effect of indomethacin was dose-dependent, reaching an optimal effect at 1 µM when 100–1000 units/ml IL-2 were employed. The effect of indomethacin on the generation of ADCC was seen in cells taken from both tumor-bearing mice and normal mice. ADCC induced by IL-2 was augmented by culturing cells from the spleen, liver and lungs, in the presence of indomethacin. ADCC induced in the presence of IL-2 and indomethacin was mediated by cells that were mainly plastic non-adherent cells and expressed the asialo-GM1 glycolipid. The potential of indomethacin in combined therapy with cytokines and specific anti-tumor monoclonal antibodies is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Brunda MJ, Herberman RB, Holden HT (1980) Inhibition of murine natural killer cell activity by prostaglandins. J Immunol 124: 2682

    Google Scholar 

  2. Eisenthal A, Rosenberg SA (1989) Systemic induction of cells mediating antibody dependent cellular cytotoxicity (ADCC) following the administration of interleukin-2 Cancer Res 49: 6953

    Google Scholar 

  3. Eisenthal A, Lafreniere R, Lefor AT, Rosenberg SA (1987) Effect of anti-B16 melanoma monoclonal antibody on established murine B16 melanoma liver metastases. Cancer Res 47: 2771

    Google Scholar 

  4. Eisenthal A, Cameron RB, Uppenkamp I, Rosenberg SA (1988) Effect of combined therapy with lymphokine-activated killer cells, interleukin 2 and specific monoclonal antibody on established B16 melanoma lung metastases. Cancer Res 48: 7140

    Google Scholar 

  5. Eisenthal A, Shiloni E, Rosenberg SA (1988) Characterization of IL-2-induced murine cells which exhibit ADCC activity. Cell Immunol 115: 257

    Google Scholar 

  6. Fulton AM (1988) Inhibition of experimental metastasis with indomethacin: Role of macrophages and natural killer cells. Prostaglandins 35: 413

    Google Scholar 

  7. Goodwin JS, Bankhurst AD, Messner RP (1977) Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell. J Exp Med 146: 1719

    Google Scholar 

  8. Henney CS, Bourne HR, Lichtenstein LM (1971) The role of 3' 5' adenosine monophosphate in the specific cytolytic activity of lymphocytes. J Immunol 108: 1526

    Google Scholar 

  9. Honda M, Steinberg AD (1984) Effects of prostaglandin E2 on responses of T-cell subsets to mitogen and autologous non-T-cell stimulation. Clin Immunol Immunopathol 33: 111

    Google Scholar 

  10. Ibayashi Y, Hoon DS, Golub SH (1987) The regulatory effect of adherent cells on lymphokine activated killer cells. Cell Immunol 110: 365

    Google Scholar 

  11. Kanar MC, Thiele DL, Ostensen M, Lipsky PE (1988) Regulation of human natural killer (NK) cell function: induction of killing of an NK-resistant renal carcinoma cell line. J Clin Immunol 8: 69

    Google Scholar 

  12. Kawase I, Komuta K, Hara H, Inoue T, Hosoe S, Ikeda T, Shirasaka T, Yokota S, Tanio Y, Masunio T, Kishimoto S (1988) Combined therapy of mice bearing a lymphokine-activated killer-resistant tumor with recombinant interleukin 2 and an antitumor monoclonal antibody capable of inducing antibody-dependent cellular cytotoxicity. Cancer Res 48: 1173

    Google Scholar 

  13. Lala PK, Parhar RS (1988) Cure of B16F10 melanoma lung metastasis in mice by chronic indomethacin therapy combined with repeated rounds of interleukin-2: characteristics of killer cells generated in situ. Cancer Res 48: 1072

    Google Scholar 

  14. Lala PK, Kennedy TG, Parhar RS (1988) Suppression of lymphocyte alloreactivity by early gestational human decidua II. Characterization of the suppressor mechanisms. Cell Immunol 116: 411

    Google Scholar 

  15. Leung KH, Mihich E (1980) Prostaglandin modulation of development of cell-mediated immunity in culture. Nature 288: 597

    Google Scholar 

  16. Murray JL, Down J, Hersh EM (1986) In vitro inhibition of interleukin-2 production by peripheral blood lymphocytes from stage III melanoma patients by prostaglandin E2: enhancement of lymphocyte proliferation by exogenous interleukin-2 plus indomethacin. J Biol Response Mod 5: 12

    Google Scholar 

  17. Ogawa M, Mori T, Mori Y, Ueda S, Yoshida H, Kato I, Iesato K, Wakashin Y, Wakashin M, Okuda K (1988) Inhibitory effects of prostaglandin E1 on T-cell mediated cytotoxicity against isolated mouse liver cells. Gastroenterology 94: 1024

    Google Scholar 

  18. Okumura Y, Ishibashi H, Shirahama M, Kurokawa S, Kudo J, Okubo H, Niho Y (1987) Kupffer cells modulate natural killer cell activity in vitro by producing prostaglandins. Cell Immunol 107: 89

    Google Scholar 

  19. Parhar RS, Lala PK (1987) Amelioration of B16F10 melanoma lung metastasis in mice by a combination therapy with indomethacin and interleukin-2. J Exp Med 165: 14

    Google Scholar 

  20. Pedersen BK, Oxholm P, Klarlund K (1986) Characterization of the in vivo and in vitro effects of indomethacin on human natural killer cell activity. Allergy 41: 532

    Google Scholar 

  21. Pedersen BK, Kharazmi A, Svenson M (1988) Down-regulation of natural killer cell activity by autologous polymorphonuclear leucocytes. Role of indomethacin. Allergy 43: 17

    Google Scholar 

  22. Pelus LM, Ottmann OG, Nocka KH (1988) Synergistic inhibition of human bone marrow granulocyte-macrophage progenitor cells by prostaglandin E and recombinant interferon-α, and γ, and an effect mediated by tumor necrosis factor. J Immunol 140: 479

    Google Scholar 

  23. Remick DG, Larrick JW, Nguyen DT, Kunkel SL (1987) Stimulation of prostaglandin E2 and thromboxane B2 production by human monocytes in response to interleukin-2. Biochem Biophys Res Commun 147: 86

    Google Scholar 

  24. Remick DG, Kunkel SL, Higashi GI, Hiserodt JC (1988) Suppression of natural killer cytolytic activity in mice undergoing pulmonary granulomatous inflammation. J Immunol 140: 2225

    Google Scholar 

  25. Rita M, Young I, Young ME, Kim K (1988) Regulation of tumor-induced myelopoiesis and the associated immune suppressor cells in mice bearing metastatic Lewis lung carcinoma by prostaglandin E2. Cancer Res 48: 6826

    Google Scholar 

  26. Rosenberg SA, Grimm EA, McGrogan M, Doyle M, Kawasaki E, Koths K, Mark DF (1984) Biological activity of recombinant human interleukin 2 produced inEscherichia coli. Science 223: 1412

    Google Scholar 

  27. Sachs DH, Cone JL (1973) A murine B-cell alloantigen determined by gene(s) linked to the major histocompatibility complex. J Exp Med 138: 1289

    Google Scholar 

  28. Shiloni E, Eisenthal A, Sachs D, Rosenberg SA (1987) Antibody-dependent cellular cytotoxicity mediated by murine lymphocytes activated in recombinant interleukin 2. J Immunol 138: 1992

    Google Scholar 

  29. Shultz RM, Pavlidis NA, Slylos WA, Chirigos MA (1978) Regulation of macrophage tumoricidal functions: a role of prostaglandins of E-series. Science 202: 320

    Google Scholar 

  30. Sileghem M, Darji A, Remels L, Hamers R, Baetselier PD (1989) Different mechanism account for the suppression of interleukin 2 production and the suppression of interleukin 2 receptor expression in trypanosoma brucei-infected mice. Eur J Immunol 19: 119

    Google Scholar 

  31. Smith KA, Lachman LB, Oppenheim JJ, Favata FM (1980) The functional relationship of the interleukins. J Exp Med 151: 1551

    Google Scholar 

  32. Talmadge JE, Phillips H, Schindler J, Tribble H, Pennington R (1987) Systemic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease. Cancer Res 47: 5725

    Google Scholar 

  33. Voth R, Chemielarczyk W, Storch E, Kirchner H (1986) Induction of natural killer cell activity in mice by injection of indomethacin. Nat Immun Cell Growth Regul 5: 314

    Google Scholar 

  34. Webb DR, Nowowiejski I (1975) The role of prostaglandins in the control of primary 19S immune response to SRBC. Cell Immunol 33: 1

    Google Scholar 

  35. Weber JS, Jay G, Tanaka K, Rosenberg SA (1987) Immunotherapy of a murine tumor with interleukin-2 increased sensitivity after MHC class I gene transfection. J Exp Med 166: 1716

    Google Scholar 

  36. Young MR, Newby M (1986) Differential induction of suppressor macrophages by cloned Lewis lung carcinoma variants in mice. J Natl Cancer Inst 77: 1255

    Google Scholar 

  37. Young MR, Endicott RA, Duffie GP, Wepsic HT (1987) Suppressor alveolar macrophages in mice bearing metastatic Lewis lung carcinoma tumors. J Leukocyte Biol 42: 682

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B42, 20892, Bethesda, Maryland, USA

    Avi Eisenthal

Authors
  1. Avi Eisenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eisenthal, A. Indomethacin up-regulates the generation of lymphokine-activated killer-cell activity and antibody-dependent cellular cytotoxicity mediated by interleukin-2. Cancer Immunol Immunother 31, 342–348 (1990). https://doi.org/10.1007/BF01741405

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01741405

Keywords

Search

Navigation