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. 1991 Aug;73(4):450–456.

Activation of human natural killer cells by lipopolysaccharide and generation of interleukin-1 alpha, beta, tumour necrosis factor and interleukin-6. Effect of IL-1 receptor antagonist.

P Conti 1, R A Dempsey 1, M Reale 1, R C Barbacane 1, M R Panara 1, M Bongrazio 1, J W Mier 1
PMCID: PMC1384575  PMID: 1833315

Abstract

The presence in the body of an antigen species or a bacterial lipopolysaccharide (LPS) has a pleiotropic effect on the immune system activating macrophages, lymphocytes and natural killer (NK) cells. Recently it has been reported that human macrophages not only secrete interleukin-1 (IL-1) but also its inhibitor, called IL-1 receptor antagonist (IL-1ra), structurally similar to IL-1 beta, but with no IL-1-like activity and which binds to the IL-1 receptor. In this study we show that LPS stimulates NK cell activity and IL-1ra potentiates the stimulatory effect of human recombinant interleukin-2 (hrIL-2) on NK cell activity. In addition, we found that hrIL-1ra inhibits DNA synthesis in lymphocyte culture stimulated with phytohaemagglutinin (PHA) (20 micrograms/ml), presumably via IL-1 inhibition. We also found that LPS is a potent stimulator of monokines: IL-6, tumour necrosis factor-alpha (TNF-alpha), and IL-1 beta, as determined by radioimmunoassay method, and interferon-gamma (IFN-gamma), IL-2, TNF-alpha and IL-1 alpha, as determined by ELISA method, in peripheral blood mononuclear cells (PBMC). We used PBMC as effector cells since LPS requires the presence of accessory cells to activate lymphocytes and bind to the HLA-DR molecule on accessory cells. The effect of LPS on PBMC cytotoxicity has been compared with an endotoxin-free extract of Escherichia coli, OM-8990, which did not provoke cytokine production nor did it cause enhancement of NK cell activity. We found that human recombinant IL-1ra potentiates the stimulatory effect of IL-2 on NK cell activity, similar to hrIL-1 beta. The potentiation of IL-2 in stimulating NK cell activity by IL-1ra is not yet understood. Since IL-1ra is a part of the IL-1 family, it may work in a similar fashion to IL-1, which also potentiates IL-2 to enhance NK cell activity but has been shown not to be directly important in tumour cell killing. In addition, hrIL-1ra can amplify the effect of IL-2 on NK activity, possibly by inhibiting the cyclo-oxygenase products, which are immunosuppressive and are generated in antigen-stimulated PBMC cultures. The generation of IFN-gamma by PBMC after treatment with LPS strongly suggests that the enhancement of NK cell activity may be indirectly due to IFN production.

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Selected References

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  1. Arend W. P., Welgus H. G., Thompson R. C., Eisenberg S. P. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990 May;85(5):1694–1697. doi: 10.1172/JCI114622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baumgartner J. D., Heumann D., Gerain J., Weinbreck P., Grau G. E., Glauser M. P. Association between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific antibodies with core LPS antibodies. J Exp Med. 1990 Mar 1;171(3):889–896. doi: 10.1084/jem.171.3.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ben Aribia M. H., Leroy E., Lantz O., Métivier D., Autran B., Charpentier B., Hercend T., Senik A. rIL 2-induced proliferation of human circulating NK cells and T lymphocytes: synergistic effects of IL 1 and IL 2. J Immunol. 1987 Jul 15;139(2):443–451. [PubMed] [Google Scholar]
  4. Brahmi Z., Bray R. A., Abrams S. I. Evidence for an early calcium-independent event in the activation of the human natural killer cell cytolytic mechanism. J Immunol. 1985 Dec;135(6):4108–4113. [PubMed] [Google Scholar]
  5. Carter D. B., Deibel M. R., Jr, Dunn C. J., Tomich C. S., Laborde A. L., Slightom J. L., Berger A. E., Bienkowski M. J., Sun F. F., McEwan R. N. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990 Apr 12;344(6267):633–638. doi: 10.1038/344633a0. [DOI] [PubMed] [Google Scholar]
  6. Conti P., Reale M., Angeletti P. U., Dinarello C. A. Restoration of anti-interleukin-1 depressed natural killer activity by human recombinant interferon alpha or gamma, human recombinant interleukin-2 and indomethacin. Int J Immunopharmacol. 1988;10(8):907–911. doi: 10.1016/0192-0561(88)90035-5. [DOI] [PubMed] [Google Scholar]
  7. Dempsey R. A., Dinarello C. A., Mier J. W., Rosenwasser L. J., Allegretta M., Brown T. E., Parkinson D. R. The differential effects of human leukocyte pyrogen/lymphocyte-activating factor, T cell growth factor, and interferon on human natural killer activity. J Immunol. 1982 Dec;129(6):2504–2510. [PubMed] [Google Scholar]
  8. Dinarello C. A., Conti P., Mier J. W. Effects of human interleukin-1 on natural killer cell activity: is fever a host defense mechanism for tumor killing? Yale J Biol Med. 1986 Mar-Apr;59(2):97–106. [PMC free article] [PubMed] [Google Scholar]
  9. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  10. Essner R., Rhoades K., McBride W. H., Morton D. L., Economou J. S. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol. 1989 Jun 1;142(11):3857–3861. [PubMed] [Google Scholar]
  11. Fischer H., Dohlsten M., Andersson U., Hedlund G., Ericsson P., Hansson J., Sjögren H. O. Production of TNF-alpha and TNF-beta by staphylococcal enterotoxin A activated human T cells. J Immunol. 1990 Jun 15;144(12):4663–4669. [PubMed] [Google Scholar]
  12. Flad H. D., Loppnow H., Feist W., Wang M. H., Brade H., Kusumoto S., Rietschel E. T., Ulmer A. J. Interleukin 1 and tumor necrosis factor: studies on the induction by lipopolysaccharide partial structures. Lymphokine Res. 1989 Fall;8(3):235–238. [PubMed] [Google Scholar]
  13. Forbes J. T., Bretthauer R. K., Oeltmann T. N. Mannose 6-, fructose 1-, and fructose 6-phosphates inhibit human natural cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5797–5801. doi: 10.1073/pnas.78.9.5797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  15. Henney C. S., Kuribayashi K., Kern D. E., Gillis S. Interleukin-2 augments natural killer cell activity. Nature. 1981 May 28;291(5813):335–338. doi: 10.1038/291335a0. [DOI] [PubMed] [Google Scholar]
  16. Herberman R. R., Ortaldo J. R., Bonnard G. D. Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity. Nature. 1979 Jan 18;277(5693):221–223. doi: 10.1038/277221a0. [DOI] [PubMed] [Google Scholar]
  17. Kawase I., Brooks C. G., Kuribayashi K., Olabuenaga S., Newman W., Gillis S., Henney C. S. Interleukin 2 induces gamma-interferon production: participation of macrophages and NK-like cells. J Immunol. 1983 Jul;131(1):288–292. [PubMed] [Google Scholar]
  18. Klimpel G. R., Niesel D. W., Asuncion M., Klimpel K. D. Natural killer cell activation and interferon production by peripheral blood lymphocytes after exposure to bacteria. Infect Immun. 1988 Jun;56(6):1436–1441. doi: 10.1128/iai.56.6.1436-1441.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ku G., Doherty N. S., Schmidt L. F., Jackson R. L., Dinerstein R. J. Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J. 1990 Apr 1;4(6):1645–1653. doi: 10.1096/fasebj.4.6.2318380. [DOI] [PubMed] [Google Scholar]
  20. Levin J., Poore T. E., Zauber N. P., Oser R. S. Detection of endotoxin in the blood of patients with sepsis due to gran-negative bacteria. N Engl J Med. 1970 Dec 10;283(24):1313–1316. doi: 10.1056/NEJM197012102832404. [DOI] [PubMed] [Google Scholar]
  21. Lindemann R. A., Eilber F. Activation of human natural killer cells by lipopolysaccharide from Actinobacillus actinomycetemcomitans. Arch Oral Biol. 1989;34(6):459–463. doi: 10.1016/0003-9969(89)90125-8. [DOI] [PubMed] [Google Scholar]
  22. Lise L. D., Audibert F. Immunoadjuvants and analogs of immunomodulatory bacterial structures. Curr Opin Immunol. 1989 Dec;2(2):269–274. doi: 10.1016/0952-7915(89)90199-4. [DOI] [PubMed] [Google Scholar]
  23. Lisi P. J., Chu C. W., Koch G. A., Endres S., Lonnemann G., Dinarello C. A. Development and use of a radioimmunoassay for human interleukin-1 beta. Lymphokine Res. 1987 Summer;6(3):229–244. [PubMed] [Google Scholar]
  24. Minowada J., Onuma T., Moore G. E. Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocytes. J Natl Cancer Inst. 1972 Sep;49(3):891–895. [PubMed] [Google Scholar]
  25. Morrison D. C., Ryan J. L. Bacterial endotoxins and host immune responses. Adv Immunol. 1979;28:293–450. doi: 10.1016/s0065-2776(08)60802-0. [DOI] [PubMed] [Google Scholar]
  26. Ortaldo J. R., Oldham R. K., Cannon G. C., Herberman R. B. Specificity of natural cytotoxic reactivity of normal human lymphocytes against a myeloid leukemia cell line. J Natl Cancer Inst. 1977 Jul;59(1):77–82. doi: 10.1093/jnci/59.1.77. [DOI] [PubMed] [Google Scholar]
  27. Rolstad B., Herberman R. B., Reynolds C. W. Natural killer cell activity in the rat. V. The circulation patterns and tissue localization of peripheral blood large granular lymphocytes (LGL). J Immunol. 1986 Apr 15;136(8):2800–2808. [PubMed] [Google Scholar]
  28. Rosenthal M. Effect of a bacterial extract on cellular and humoral immune responses in humans. J Immunopharmacol. 1986;8(3):315–325. doi: 10.3109/08923978609026492. [DOI] [PubMed] [Google Scholar]
  29. Salata R. A., Kleinhenz M. E., Schacter B. Z., Ellner J. J. Augmentation of natural killer cell activity by lipopolysaccharide through separable effects on the binding of nonadherent lymphocytes to tumor targets and tumor killing. Cancer Res. 1984 Mar;44(3):1044–1047. [PubMed] [Google Scholar]
  30. Scala G., Allavena P., Djeu J. Y., Kasahara T., Ortaldo J. R., Herberman R. B., Oppenheim J. J. Human large granular lymphocytes are potent producers of interleukin-1. Nature. 1984 May 3;309(5963):56–59. doi: 10.1038/309056a0. [DOI] [PubMed] [Google Scholar]
  31. Schindler R., Ghezzi P., Dinarello C. A. Interferons as inhibitors of interleukin 1 induced interleukin 1 synthesis. Lymphokine Res. 1989 Fall;8(3):275–280. [PubMed] [Google Scholar]
  32. Steinhauer E. H., Doyle A. T., Kadish A. S. Human natural killer cytotoxic factor (NKCF): role of IFN-alpha. J Immunol. 1985 Jul;135(1):294–299. [PubMed] [Google Scholar]
  33. Talmadge J. E. Immunoregulation and immunostimulation of murine lymphocytes by recombinant human interleukin-2. J Biol Response Mod. 1985 Feb;4(1):18–34. [PubMed] [Google Scholar]
  34. Tarkkanen J., Saxén H., Nurminen M., Mäkelä P. H., Saksela E. Bacterial induction of human activated lymphocyte killing and its inhibition by lipopolysaccharide (LPS). J Immunol. 1986 Apr 1;136(7):2662–2669. [PubMed] [Google Scholar]
  35. Timonen T., Ortaldo J. R., Herberman R. B. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J Exp Med. 1981 Mar 1;153(3):569–582. doi: 10.1084/jem.153.3.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Timonen T., Saksela E. Isolation of human NK cells by density gradient centrifugation. J Immunol Methods. 1980;36(3-4):285–291. doi: 10.1016/0022-1759(80)90133-7. [DOI] [PubMed] [Google Scholar]
  37. Trinchieri G., Perussia B. Human natural killer cells: biologic and pathologic aspects. Lab Invest. 1984 May;50(5):489–513. [PubMed] [Google Scholar]
  38. Wahl S. M., McCartney-Francis N., Hunt D. A., Smith P. D., Wahl L. M., Katona I. M. Monocyte interleukin 2 receptor gene expression and interleukin 2 augmentation of microbicidal activity. J Immunol. 1987 Aug 15;139(4):1342–1347. [PubMed] [Google Scholar]
  39. Young M. R., Wheeler E., Newby M. Macrophage-mediated suppression of natural killer cell activity in mice bearing Lewis lung carcinoma. J Natl Cancer Inst. 1986 Apr;76(4):745–750. doi: 10.1093/jnci/76.4.745. [DOI] [PubMed] [Google Scholar]
  40. van der Meer J. W., Endres S., Lonnemann G., Cannon J. G., Ikejima T., Okusawa S., Gelfand J. A., Dinarello C. A. Concentrations of immunoreactive human tumor necrosis factor alpha produced by human mononuclear cells in vitro. J Leukoc Biol. 1988 Mar;43(3):216–223. doi: 10.1002/jlb.43.3.216. [DOI] [PubMed] [Google Scholar]

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