Abstract
The present study examined the ability of human monocytes to produce reactive oxygen intermediates after a contact with tumour cells. Monocytes generated oxygen radicals, as measured by luminol-enhanced chemiluminescence and superoxide anion production, after stimulation with the tumour, but not with untransformed, cells. The use of specific oxygen radical scavengers and inhibitors, superoxide dismutase, catalase, dimethyl sulphoxide and deferoxamine as well as the myeloperoxidase inhibitor 4-aminobenzoic acid hydrazide, indicated that chemiluminescence was dependent on the production of superoxide anion and hydroxyl radical and the presence of myeloperoxidase. The tumour cell-induced chemiluminescent response of monocytes showed different kinetics from that seen after activation of monocytes with phorbol ester. These results indicate that human monocytes can be directly stimulated by tumour cells for reactive oxygen intermediate production. Spontaneous monocyte-mediated cytotoxicity towards cancer cells was inhibited by superoxide dismutase, catalase, deferoxamine and hydrazide, implicating the role of superoxide anion, hydrogen peroxide, hydroxyl radical and hypohalite. We wish to suggest that so-called ‘spontaneous’ tumoricidal capacity of freshly isolated human monocytes may in fact be an inducible event associated with generation of reactive oxygen intermediates and perhaps other toxic mediators, resulting from a contact of monocytes with tumour cells. © 1999 Cancer Research Campaign
Keywords: monocyte, tumour cells, interactions, reactive oxygen intermediates, cytotoxicity
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- Beissert S., Bergholz M., Waase I., Lepsien G., Schauer A., Pfizenmaier K., Krönke M. Regulation of tumor necrosis factor gene expression in colorectal adenocarcinoma: in vivo analysis by in situ hybridization. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5064–5068. doi: 10.1073/pnas.86.13.5064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davies B., Edwards S. W. Interactions between human monocytes and tumour cells. Monocytes can either enhance or inhibit the growth and survival of K562 cells. Br J Cancer. 1992 Sep;66(3):463–469. doi: 10.1038/bjc.1992.296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ding A. H., Nathan C. F., Stuehr D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed] [Google Scholar]
- Ernst M., Lange A., Flad H. D., Havel A., Ennen J., Ulmer A. J. Dissociation of responses measured by natural cytotoxicity and chemiluminescence. Eur J Immunol. 1984 Jul;14(7):634–639. doi: 10.1002/eji.1830140710. [DOI] [PubMed] [Google Scholar]
- Galligioni E., Quaia M., Spada A., Favaro D., Santarosa M., Talamini R., Monfardini S. Activation of cytolytic activity in peripheral blood monocytes of renal cancer patients against non-cultured autologous tumor cells. Int J Cancer. 1993 Sep 30;55(3):380–385. doi: 10.1002/ijc.2910550307. [DOI] [PubMed] [Google Scholar]
- Hara N., Ichinose Y., Asoh H., Yano T., Kawasaki M., Ohta M. Superoxide anion-generating activity of polymorphonuclear leukocytes and monocytes in patients with lung cancer. Cancer. 1992 Apr 1;69(7):1682–1687. doi: 10.1002/1097-0142(19920401)69:7<1682::aid-cncr2820690707>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
- Hasday J. D., Shah E. M., Lieberman A. P. Macrophage tumor necrosis factor-alpha release is induced by contact with some tumors. J Immunol. 1990 Jul 1;145(1):371–379. [PubMed] [Google Scholar]
- Hruby Z., Beck K. F. Cytotoxic effect of autocrine and macrophage-derived nitric oxide on cultured rat mesangial cells. Clin Exp Immunol. 1997 Jan;107(1):76–82. doi: 10.1046/j.1365-2249.1997.d01-906.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ioannidis I., de Groot H. Cytotoxicity of nitric oxide in Fu5 rat hepatoma cells: evidence for co-operative action with hydrogen peroxide. Biochem J. 1993 Dec 1;296(Pt 2):341–345. doi: 10.1042/bj2960341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jänicke R., Männel D. N. Distinct tumor cell membrane constituents activate human monocytes for tumor necrosis factor synthesis. J Immunol. 1990 Feb 1;144(3):1144–1150. [PubMed] [Google Scholar]
- Jättelä M., Wissing D. Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection. J Exp Med. 1993 Jan 1;177(1):231–236. doi: 10.1084/jem.177.1.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- King C. C., Jefferson M. M., Thomas E. L. Secretion and inactivation of myeloperoxidase by isolated neutrophils. J Leukoc Biol. 1997 Mar;61(3):293–302. doi: 10.1002/jlb.61.3.293. [DOI] [PubMed] [Google Scholar]
- Klassen D. K., Sagone A. L., Jr Evidence for both oxygen and non-oxygen dependent mechanisms of antibody sensitized target cell lysis by human monocytes. Blood. 1980 Dec;56(6):985–992. [PubMed] [Google Scholar]
- Lanza F., Fietta A., Spisani S., Castoldi G. L., Traniello S. Does a relationship exist between neutrophil myeloperoxidase deficiency and the occurrence of neoplasms? J Clin Lab Immunol. 1987 Apr;22(4):175–180. [PubMed] [Google Scholar]
- Leek R. D., Lewis C. E., Whitehouse R., Greenall M., Clarke J., Harris A. L. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996 Oct 15;56(20):4625–4629. [PubMed] [Google Scholar]
- Mantovani A., Bottazzi B., Colotta F., Sozzani S., Ruco L. The origin and function of tumor-associated macrophages. Immunol Today. 1992 Jul;13(7):265–270. doi: 10.1016/0167-5699(92)90008-U. [DOI] [PubMed] [Google Scholar]
- Martin J. H., Edwards S. W. Changes in mechanisms of monocyte/macrophage-mediated cytotoxicity during culture. Reactive oxygen intermediates are involved in monocyte-mediated cytotoxicity, whereas reactive nitrogen intermediates are employed by macrophages in tumor cell killing. J Immunol. 1993 Apr 15;150(8 Pt 1):3478–3486. [PubMed] [Google Scholar]
- Mavier P., Edgington T. S. Human monocyte-mediated tumor cytotoxicity. I. Demonstration of an oxygen-dependent myeloperoxidase-independent mechanism. J Immunol. 1984 Apr;132(4):1980–1986. [PubMed] [Google Scholar]
- McLachlan J. A., Serkin C. D., Morrey K. M., Bakouche O. Antitumoral properties of aged human monocytes. J Immunol. 1995 Jan 15;154(2):832–843. [PubMed] [Google Scholar]
- McNally J. A., Bell A. L. Myeloperoxidase-based chemiluminescence of polymorphonuclear leukocytes and monocytes. J Biolumin Chemilumin. 1996 Mar-Apr;11(2):99–106. doi: 10.1002/(SICI)1099-1271(199603)11:2<99::AID-BIO404>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
- Nakabo Y., Pabst M. J. C2-ceramide and C6-ceramide inhibited priming for enhanced release of superoxide in monocytes, but had no effect on the killing of leukaemic cells by monocytes. Immunology. 1997 Apr;90(4):477–482. doi: 10.1046/j.1365-2567.1997.d01-2189.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C. F., Silverstein S. C., Brukner L. H., Cohn Z. A. Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity. J Exp Med. 1979 Jan 1;149(1):100–113. doi: 10.1084/jem.149.1.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C., Cohn Z. Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages. J Exp Med. 1980 Jul 1;152(1):198–208. doi: 10.1084/jem.152.1.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Palomba L., Sestili P., Cattabeni F., Azzi A., Cantoni O. Prevention of necrosis and activation of apoptosis in oxidatively injured human myeloid leukemia U937 cells. FEBS Lett. 1996 Jul 15;390(1):91–94. doi: 10.1016/0014-5793(96)00634-5. [DOI] [PubMed] [Google Scholar]
- Pazdrak K., Justement L., Alam R. Mechanism of inhibition of eosinophil activation by transforming growth factor-beta. Inhibition of Lyn, MAP, Jak2 kinases and STAT1 nuclear factor. J Immunol. 1995 Nov 1;155(9):4454–4458. [PubMed] [Google Scholar]
- Pericle F., Sconocchia G., Titus J. A., Segal D. M. CD44 is a cytotoxic triggering molecule on human polymorphonuclear cells. J Immunol. 1996 Nov 15;157(10):4657–4663. [PubMed] [Google Scholar]
- Pick E., Mizel D. Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. J Immunol Methods. 1981;46(2):211–226. doi: 10.1016/0022-1759(81)90138-1. [DOI] [PubMed] [Google Scholar]
- Rothe G., Gabriel H., Kovacs E., Klucken J., Stöhr J., Kindermann W., Schmitz G. Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1437–1447. doi: 10.1161/01.atv.16.12.1437. [DOI] [PubMed] [Google Scholar]
- Siedlar M., Stachura J., Szczepanik A., Popiela T., Mattei M., Vendetti S., Colizzi V., Zembala M. Characterization of human pancreatic adenocarcinoma cell line with high metastatic potential in SCID mice. Invasion Metastasis. 1995;15(1-2):60–69. [PubMed] [Google Scholar]
- Sun Y., Oberley L. W., Elwell J. H., Sierra-Rivera E. Antioxidant enzyme activities in normal and transformed mouse liver cells. Int J Cancer. 1989 Dec 15;44(6):1028–1033. doi: 10.1002/ijc.2910440615. [DOI] [PubMed] [Google Scholar]
- Trulson A., Nilsson S., Brekkan E., Venge P. Patients with renal cancer have a larger proportion of high-density blood monocytes with increased lucigenin-enhanced chemiluminescence. Inflammation. 1994 Feb;18(1):99–105. doi: 10.1007/BF01534602. [DOI] [PubMed] [Google Scholar]
- Trulson A., Nilsson S., Venge P. Lucigenin-enhanced chemiluminescence in blood is increased in cancer. Am J Clin Pathol. 1989 Apr;91(4):441–445. doi: 10.1093/ajcp/91.4.441. [DOI] [PubMed] [Google Scholar]
- Utsugi T., Schroit A. J., Connor J., Bucana C. D., Fidler I. J. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res. 1991 Jun 1;51(11):3062–3066. [PubMed] [Google Scholar]
- Zembala M., Czupryna A., Wieckiewicz J., Jasinski M., Pryjma J., Ruggiero I., Siedlar M., Popiela T. Tumour-cell-induced production of tumour necrosis factor by monocytes of gastric cancer patients receiving BCG immunotherapy. Cancer Immunol Immunother. 1993;36(2):127–132. doi: 10.1007/BF01754413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zembala M., Siedlar M., Marcinkiewicz J., Pryjma J. Human monocytes are stimulated for nitric oxide release in vitro by some tumor cells but not by cytokines and lipopolysaccharide. Eur J Immunol. 1994 Feb;24(2):435–439. doi: 10.1002/eji.1830240225. [DOI] [PubMed] [Google Scholar]
- Zembala M., Siedlar M., Ruggiero I., Wieckiewicz J., Mytar B., Mattei M., Colizzi V. The MHC class-II and CD44 molecules are involved in the induction of tumour necrosis factor (TNF) gene expression by human monocytes stimulated with tumour cells. Int J Cancer. 1994 Jan 15;56(2):269–274. doi: 10.1002/ijc.2910560221. [DOI] [PubMed] [Google Scholar]
- van Muijen G. N., Danen E. H., Veerkamp J. H., Ruiter D. J., Lesley J., van den Heuvel L. P. Glycoconjugate profile and CD44 expression in human melanoma cell lines with different metastatic capacity. Int J Cancer. 1995 Apr 10;61(2):241–248. doi: 10.1002/ijc.2910610217. [DOI] [PubMed] [Google Scholar]