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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1989 Jan;30(1):57–64. doi: 10.1007/BF01665031

Interferon-γ (IFN-γ) and interleukin-2 in the generation of lymphokine-activated killer cell cytotoxicity — IFN-γ-induced suppressive activity

Michel Toledano 1, Claire Mathiot 1,3, Jean Michon 1, Georges Andreu 4, Danielle Lando 5, Maud Brandely 5, Wolf H Fridman 1,
PMCID: PMC11038676  PMID: 2513112

Abstract

Incubation of human lymphocytes with recombinant interleukin-2 (rIL-2) results in the generation of lymphokine-activated killer (LAK) cells capable of lysing a wide variety of tumor cells. The present study was undertaken to examine the effect of recombinant γ interferon (rIFN-γ) on LAK cell cytotoxicity generated from different peripheral blood mononuclear cell (PBMC) subpopulations. When unseparated PBMC were stimulated by rIL-2 and rIFN-γ, the latter induced a transient enhancement after 2 days followed by a suppression of LAK cell cytotoxicity at day 6. Enhancement of LAK cell cytotoxicity was moderate and inconstant, whereas the inhibition was strong and observed with all the donors tested. This suppression was not associated with a decrease in the [3H]thymidine uptake. PBMC depleted of adherent cells were more sensitive to the stimulation by rIL-2 and the induced cytotoxicity was not modified by rIFN-γ. Monocyte-enriched plastic-adherent cells, when incubated with rIL-2 and rIFN-γ, became cytotoxic after 2–3 days of culture and inhibited LAK cell activity after 5–6 days. Collectively, our results suggest that rIFN-γ affects LAK cell cytotoxicity through the activation of plastic-adherent, monocyte-rich, cells which modulate natural killer cells, first in a positive, then in a negative way.

Keywords: Natural Killer, Interferon, Natural Killer Cell, Peripheral Blood Mononuclear Cell, Thymidine

References

  • 1.Billard C, Ferbus D, Kolb JP, Rosa F, Perrot JY, Merlin G, Janiaud P, Raynaud N, Thang MN, Fellous M, Aguet M, Fridman WH, Falcoff E. Qualitative differences in effects of recombinant α-, β- and γ-interferons on human peripheral blood leukocytesin vitro . Ann Inst Pasteur Immunol. 1986;137:259. doi: 10.1016/s0771-050x(86)80045-6. [DOI] [PubMed] [Google Scholar]
  • 2.Bloom ET, Babbitt JT. Monocyte-mediated augmentation of human natural cell-mediated cytotoxicity. Cell Immunol. 1985;91:21. doi: 10.1016/0008-8749(85)90028-0. [DOI] [PubMed] [Google Scholar]
  • 3.Brunda MJ, Tarnowski D, Davatelis V. Interaction of recombinant interferons with recombinant interleukin-2: differential effects on natural killer cell activity and interleukin-2 activated killer cells. Int J Cancer. 1986;37:787. doi: 10.1002/ijc.2910370522. [DOI] [PubMed] [Google Scholar]
  • 4.Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of Natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Handa K, Suzuki R, Matsui H, Shimizu Y, Kumagai K. Natural killer (NK) cells as a responder to interleukin-2 (IL2). II. IL2-induced interferon γ production. J Immunol. 1983;130:988. [PubMed] [Google Scholar]
  • 6.Heberman RB, Hiserodt J, Vujanovic N. Lymphokineactivated killer cell activity. Characteristics of effector cells and their progenitors in blood and spleen. Immunol Today. 1987;8:178. doi: 10.1016/0167-5699(87)90035-1. [DOI] [PubMed] [Google Scholar]
  • 7.Herrmann F, Cannistra SA, Levine H, Griffin JD. Expression of interleukin-2 receptors and binding of interleukin-2 by gamma interferon-induced human leukemic and normal monocytic cells. J Exp Med. 1985;162:1111. doi: 10.1084/jem.162.3.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Holter W, Grunow R, Stockinger H, Knapp W. Recombinant interferon-γ induces interleukin-2 receptors on human peripheral blood monocytes. J Immunol. 1986;136:2171. [PubMed] [Google Scholar]
  • 9.Hoyer M, Meineke T, Lewis W, Zwilling B, Rinehart J. Characterization and modulation of human lymphokine (interleukin-2) activated killer cell induction. Cancer Res. 1986;46:2834. [PubMed] [Google Scholar]
  • 10.Itoh K, Shiiba K, Shimizu Y, Suzuki R, Kumagai K. Generation of activated killer (AK) cells by recombinant interleukin-2 (rIL-2) in collaboration with interferon-γ (IFN-γ) J Immunol. 1985;134:3124. [PubMed] [Google Scholar]
  • 11.Koren HS, Anderson SJ, Fischer DG, Copeland CS, Jensen PJ. Regulation of human natural killing. I. The role of monocytes, interferon and prostaglandins. J Immunol. 1981;127:2007. [PubMed] [Google Scholar]
  • 12.Le J, Prensky W, Yip YK, Chang Z, Hoffman T, Stevenson HC, Balazs I, Sadlik JR, Vilcek J. Activation of human monocyte cytotoxicity by natural and recombinant immune interferon. J Immunol. 1983;131:2821. [PubMed] [Google Scholar]
  • 13.Malkovsky M, Loveland B, North M, Asherson GL, Gao L, Ward P, Fiers W. Recombinant interleukin-2 directly augments the cytotoxicity of human monocytes. Nature. 1987;325:262. doi: 10.1038/325262a0. [DOI] [PubMed] [Google Scholar]
  • 14.Mazumder A, Rosenberg SA. Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activatedin vitro by interleukin 2. J Exp Med. 1984;159:495. doi: 10.1084/jem.159.2.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mazumder A, Agah R, Malloy B. Interleukin 2 (IL2) synergizes with γ-interferon (IFN-γ) to generate LAK cellsin vitro andin vivo . AACR Proc Cancer Res. 1987;28:365. [Google Scholar]
  • 16.Nedwin GE, Svedersky LP, Bringman TS, Palladino MA, Jr, Goeddel DV. Effect of interleukin 2, interferon-γ and mitogens on the production of tumor necrosis factors α and β. J Immunol. 1985;135:2492. [PubMed] [Google Scholar]
  • 17.Nii A, Sone S, Utsugi T, Yanagawa H, Ogura T. Upand down-regulation of human lymphokine (IL2)-activated killer cell induction by monocytes, depending on their functional state. Int J Cancer. 1988;41:33. doi: 10.1002/ijc.2910410108. [DOI] [PubMed] [Google Scholar]
  • 18.Oshimi K, Oshimi Y, Satake M, Mizoguchi H. Natural killer-mediated lysis of normal and malignant target cells, and its regulation by monocytes. J Exp Med. 1985;162:472. doi: 10.1084/jem.162.2.472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ostensen ME, Thiele DL, Lipsky PE. Tumor necrosis factor-α enhances cytolytic activity of human natural killer cells. J Immunol. 1987;138:4185. [PubMed] [Google Scholar]
  • 20.Owen-Schaub LB, Gutterman JU, Grimm EA. Synergy of tumor necrosis factor and interleukin-2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor α and interleukin-2 in the generation of human lymphokine-activated killer cell cytotoxicity. Cancer Res. 1988;48:788. [PubMed] [Google Scholar]
  • 21.Rosenberg SA, Lotze MT. Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Ann Rev Immunol. 1986;3:681. doi: 10.1146/annurev.iy.04.040186.003341. [DOI] [PubMed] [Google Scholar]
  • 22.Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316:889. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 23.Sayers JT, Mason AT, Ortaldo JR. Regulation of human natural killer cell activity by interferon-γ: lack of a role in interleukin 2-mediated augmentation. J Immunol. 1986;136:2176. [PubMed] [Google Scholar]
  • 24.Sone S, Utsugi T, Nii A, Ogura T. Effects of human alveolar macrophages on the induction of lymphokine (IL2)-activated killer cells. J Immunol. 1987;139:29. [PubMed] [Google Scholar]
  • 25.Sone S, Utsugi T, Nii A, Ogura T. Differential effects of recombinant interferons α, β and γ on induction of human lymphokine (IL2)-activated killer activity. J Natl Cancer Inst. 1988;80:425. doi: 10.1093/jnci/80.6.425. [DOI] [PubMed] [Google Scholar]
  • 26.Svedersky LP, Shepard HM, Spencer SA, Shalaby MR, Palladino MA. Augmentation of human natural cell-mediated cytotoxicity by recombinant human interleukin 2. J Immunol. 1984;133:714. [PubMed] [Google Scholar]
  • 27.West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med. 1987;316:898. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]

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