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. 1988 Aug;27(1):7–12. doi: 10.1007/BF00205751

Destruction of tumor cells by monokines released from activated human blood monocytes: evidence for parallel and additive effects of IL-1 and TNF

Yukito Ichinose 1,✉, Jerry Y Tsao 1, Isaiah J Fidler 1
PMCID: PMC11037964  PMID: 3260822

Abstract

The incubation of human peripheral blood monocytes with endotoxins activates the cells to lyse tumorigenic targets directly and also induces the production and release into the culture medium of factors that produce lysis of mouse-transformed fibroblasts L-929 (tumor necrosis factor (TNF)-sensitive) and human A-375 melanoma cells (interleukin-1 (IL-1)- and TNF-sensitive). Immunoblotting analysis revealed that the culture medium of endotoxin-activated but not of control monocytes contained both IL-1 and TNF with a molecular weight of 17,000 daltons each. TNF activity was determined by lysis of L-929 cells, and IL-1 activity was measured by the proliferation of D-10 cells. The production of IL-1 and TNF was concentration-dependent, and the amounts of these monokines were paralleled. The antitumor activity of the culture supernates from endotoxin-treated monocytes was significantly decreased by incubation with heterologous antisera to IL-1, TNF, or both. Recombinant human IL-1 and TNF were used in parallel experiments and as positive controls. Each monokine used produced cytotoxic effects in susceptible targets. The combination of IL-1 and TNF, which more likely resembles culture supernates of activated macrophages, produced an additive antitumor cytotoxicity effect.

Keywords: Melanoma, Tumor Necrosis Factor, Human Peripheral Blood, Blood Monocyte, Peripheral Blood Monocyte

References

  • 1.Adams DO, Kao K-J, Farb R, Pizzo SV. Effector mechanisms of cytolytically activated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neural proteases. J Immunol. 1980;124:293. [PubMed] [Google Scholar]
  • 2.Bertoglio JH, Rimsky L, Kleinerman EG, Lachman LB. B-cell line-derived interleukin 1 is cytotoxic for melanoma cells and promotes the proliferation of an astrocytoma cell line. Lymphokine Res. 1987;6:83. [PubMed] [Google Scholar]
  • 3.Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance. Science. 1986;232:977. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  • 4.Bucana C, Hoyer LC, Hobbs B, Breesman S, McDaniel M, Hanna MG., Jr Morphological evidence for the translocation of lysosomal organelles from cytotoxic macrophages into the cytoplasm of tumor target cells. Cancer Res. 1976;36:4444. [PubMed] [Google Scholar]
  • 5.Chen AR, McKinnon KP, Koren HS. Lipopolysaccharide (LPS) stimulates fresh human monocytes to lyse actinomycin D-treated WEHI-164 target cells via increased secretion of a monokine similar to tumor necrosis factor. J Immunol. 1985;135:3978. [PubMed] [Google Scholar]
  • 6.Currie GA, Basham C. Differential arginine dependence and the selective cytotoxic effects of activated macrophages for malignant cells in vitro. Br J Cancer. 1978;38:653. doi: 10.1038/bjc.1978.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Davis LG, Dibner MD, Battey JF. Protein methods. In: Davis LG, Dibner MD, Battey JF, editors. Basic methods in molecular biology. New York: Elsevier Science Publishing Co., Inc.; 1986. pp. 306–314. [Google Scholar]
  • 8.Ferluga J, Schorlemmer HU, Baptista LC, Allison AC. Production of the complement cleavage product, C3a, by activated macrophages and its tumorolytic effects. Clin Exp Immunol. 1978;31:512. [PMC free article] [PubMed] [Google Scholar]
  • 9.Fidler IJ, Kleinerman ES (1984) Lymphokine-activated human blood monocytes destroy tumor cell but not normal cells under cocultivation condition. J Clin Oncol 2937 [DOI] [PubMed]
  • 10.Fidler IJ, Fogler WE, Kleinerman ES, Saiki I. Abrogation of species specificity for activation of tumoricidal properties in macrophages by recombinant mouse or human interferon-γ encapsulated in liposomes. J Immunol. 1985;135:4289. [PubMed] [Google Scholar]
  • 11.Heicappell R, Naito S, Ichinose Y, Creasey AA, Lin LS, Fidler IJ. Cytostatic and cytolytic effects of human recombinant tumor necrosis factor on human renal cell carcinoma cell lines derived from a single surgical specimen. J Immunol. 1987;138:1634. [PubMed] [Google Scholar]
  • 12.Hibbs JB., Jr Heterocytolysis by macrophages activated by Bacillus Calmette-Guerin: Lysosome excytosis into tumor cells. Science. 1974;184:468. doi: 10.1126/science.184.4135.468. [DOI] [PubMed] [Google Scholar]
  • 13.Kildahl-Andersen O, Nissen-Meyer J. The role of monocyte cytotoxic factor (CF) in cytostasis mediated by IFN-γ-activated monocytes. Immunology. 1985;56:367. [PMC free article] [PubMed] [Google Scholar]
  • 14.Kildahl-Andersen O, Espevik T, Nissen-Meyer J. IFN-γ-induced production of monocyte cytotoxic factor. Cell Immunol. 1985;95:392. doi: 10.1016/0008-8749(85)90326-0. [DOI] [PubMed] [Google Scholar]
  • 15.Lachman LB, Dinarello CA, Llansa ND, Fidler IJ. Natural and recombinant human interleukin 1-β is cytotoxic for human melanoma cells. J Immunol. 1986;136:3098. [PubMed] [Google Scholar]
  • 16.March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, Conlon PJ, Hopp TP, Cosman D. Cloning, sequence and expression of two distinct human interleukin I complementary DNAs. Nature. 1985;315:641. doi: 10.1038/315641a0. [DOI] [PubMed] [Google Scholar]
  • 17.Matsushima K, Taguchi M, Kovacs EJ, Young HA, Oppenheim JJ. Intracellular localization of human monocyte associated interleukin 1 (IL-1) activity and release of biologically active IL-1 from monocytes by trypsin and plasmin. J Immunol. 1986;136:2883. [PubMed] [Google Scholar]
  • 18.Nathan CF. Secretory products of macrophages. J Clin Invest. 1987;79:319. doi: 10.1172/JCI112815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Nathan CF, Silverstein SC, Brukner LH, Cohn ZA. Extracellular cytolysis by activated macrophages and granulocytes II. Hydrogen peroxide as a mediator of cytotoxicity. J Exp Med. 1979;149:100. doi: 10.1084/jem.149.1.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Onozaki K, Matsushima K, Aggarwal BB, Oppenheim JJ. Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol. 1985;135:3962. [PubMed] [Google Scholar]
  • 21.Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV. Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984;312:724. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  • 22.Philip R, Epstein LB. Tumor necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, γ-interferon and interleukin-1. Nature. 1986;323:86. doi: 10.1038/323086a0. [DOI] [PubMed] [Google Scholar]
  • 23.Reidarson TH, Granger GA, Klostergaard J. Inducible macrophage cytotoxins. II. Tumor lysis mechanism involving target cell-binding proteases. J Natl Cancer Inst. 1982;69:889. [PubMed] [Google Scholar]
  • 24.Ruff MR, Gifford GE. Tumor necrosis factor. In: Pick E, editor. Lymphokines, vol 2. New York: Academic Press, Inc.; 1981. pp. 235–272. [Google Scholar]
  • 25.Ruggiero V, Baglioni C. Synergistic anti-proliferative activity of interleukin 1 and tumor necrosis factor. J Immunol. 1987;138:661. [PubMed] [Google Scholar]
  • 26.Sanderson RJ, Shepperdson FT, Vatter AE, Talmage DW. Isolation and enumeration of peripheral blood monocytes. J Immunol. 1977;118:1409. [PubMed] [Google Scholar]
  • 27.Sone S, Lopez-Berestein G, Fidler IJ. Kinetics and function of tumor cytotoxic factor(s) produced by human blood monocytes activated to the tumoricidal state. J Natl Cancer Inst. 1985;74:583. [PubMed] [Google Scholar]
  • 28.Sone S, Lopez-Berestein G, Fidler IJ. Potentiation of direct antitumor cytotoxicity and production of tumor cytologic factors in human blood monocytes by human recombinant interferon-gamma and muramyl dipeptide derivatives. Cancer Immunol Immunother. 1986;21:93. doi: 10.1007/BF00199855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985;228:149. doi: 10.1126/science.3856324. [DOI] [PubMed] [Google Scholar]
  • 30.Ziegler-Heitbrock HWL, Moller A, Linke RP, Haas JG, Rieber EP, Riethmuller G. Tumor necrosis factor as effector molecule in monocyte-mediated cytotoxicity. Cancer Res. 1986;46:5947. [PubMed] [Google Scholar]

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