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. 1982 Jun;69(6):1223–1230. doi: 10.1172/JCI110561

Medullasin enhances human natural killer cell activity.

Y Aoki, M Sumiya, K Oshimi
PMCID: PMC370194  PMID: 6177714

Abstract

Medullasin, a new serine protease found in bone marrow cells, increased markedly human natural killer cell activity. Whereas the natural killer cell activity measured immediately after the treatment with medullasin remained almost on the same level as the control, an incubation at 37 degrees C for several hours increased markedly the natural killer cell activity of the lymphocytes treated with medullasin. Enhancement of the natural cytotoxicity was caused by the treatment with physiologic concentrations of the protease (5-20 micrograms/ml). Inhibitors of medullasin such as phenylmethylsulfonyl fluoride and elastatinal prevented the activation of natural cytotoxicity. Depletion of lymphocytes bearing Fc receptors for IgG abolished the enhancement of natural killer cell activity by medullasin. Interferon activity was not detected in the supernatant of lymphocyte cultures stimulated with medullasin. The medullasin enhanced further the natural killer cell activity of lymphocytes stimulated with interferon. Medullasin activity was detected neither in unstimulated nor stimulated (by concanavalin A or phytohemagglutinin) human lymphocytes. The protease was released easily from human mature granulocytes into culture medium. It is considered from these results that the level of human natural killer cell activity is regulated by medullasin released by mature granulocytes.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoki Y. Crystallization and characterization of a new protease in mitochondria of bone marrow cells. J Biol Chem. 1978 Mar 25;253(6):2026–2032. [PubMed] [Google Scholar]
  2. Aoki Y. Multiple enzymatic defects in mitochondria in hematological cells of patients with primary sideroblastic anemia. J Clin Invest. 1980 Jul;66(1):43–49. doi: 10.1172/JCI109833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aoki Y., Muranaka S., Nakabayashi K., Ueda Y. delta-Aminolevulinic acid synthetase in erythroblasts of patients with pyridoxine-responsive anemia. Hypercatabolism caused by the increased susceptibility to the controlling protease. J Clin Invest. 1979 Nov;64(5):1196–1203. doi: 10.1172/JCI109573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chang T. W., Eisen H. N. Effects of N alpha-tosyl-L-lysyl-chloromethylketone on the activity of cytotoxic T lymphocytes. J Immunol. 1980 Mar;124(3):1028–1033. [PubMed] [Google Scholar]
  5. Eremin O., Ashby J., Stephens J. P. Human natural cytotoxicity in the blood and lymphoid organs of healthy donors and patients with malignant disease. Int J Cancer. 1978 Jan 15;21(1):35–41. doi: 10.1002/ijc.2910210108. [DOI] [PubMed] [Google Scholar]
  6. Ferluga J., Asherson G. L., Becker E. L. The effect of organophosphorus inhibitors, p-nitrophenol and cytochalasin B on cytotoxic killing of tumour cells by immune spleen cells, and the effect of shaking. Immunology. 1972 Oct;23(4):577–590. [PMC free article] [PubMed] [Google Scholar]
  7. Fuyama S., Sendo F., Watabe S., Seiji K., Arai S. Inhibition of mouse natural killer activity by cholera toxin. Gan. 1981 Feb;72(1):141–144. [PubMed] [Google Scholar]
  8. Haller O., Hansson M., Kiessling R., Wigzell H. Role of non-conventional natural killer cells in resistance against syngeneic tumour cells in vivo. Nature. 1977 Dec 15;270(5638):609–611. doi: 10.1038/270609a0. [DOI] [PubMed] [Google Scholar]
  9. Hatcher V. B., Oberman M. S., Lazarus G. S., Grayzel A. I. A cytotoxic proteinase isolated from human lymphocytes. J Immunol. 1978 Feb;120(2):665–670. [PubMed] [Google Scholar]
  10. Havell E. A., Vilcek J. Production of high-titered interferon in cultures of human diploid cells. Antimicrob Agents Chemother. 1972 Dec;2(6):476–484. doi: 10.1128/aac.2.6.476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Herberman R. B., Nunn M. E., Holden H. T., Staal S., Djeu J. Y. Augmentation of natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic target cells. Int J Cancer. 1977 Apr 15;19(4):555–564. doi: 10.1002/ijc.2910190417. [DOI] [PubMed] [Google Scholar]
  13. Herberman R. B., Nunn M. E., Lavrin D. H., Asofsky R. Effect of antibody to theta antigen on cell-mediated immunity induced in syngeneic mice by murine sarcoma virus. J Natl Cancer Inst. 1973 Nov;51(5):1509–1512. doi: 10.1093/jnci/51.5.1509. [DOI] [PubMed] [Google Scholar]
  14. Huddlestone J. R., Merigan T. C., Jr, Oldstone M. B. Induction and kinetics of natural killer cells in humans following interferon therapy. Nature. 1979 Nov 22;282(5737):417–419. doi: 10.1038/282417a0. [DOI] [PubMed] [Google Scholar]
  15. Hudig D., Haverty T., Fulcher C., Redelman D., Mendelsohn J. Inhibition of human natural cytotoxicity by macromolecular antiproteases. J Immunol. 1981 Apr;126(4):1569–1574. [PubMed] [Google Scholar]
  16. Kiessling R., Klein E., Wigzell H. "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975 Feb;5(2):112–117. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
  17. Kiuchi M., Takasugi M. The nonselective cytotoxic cell (N cell). J Natl Cancer Inst. 1976 Mar;56(3):575–582. doi: 10.1093/jnci/56.3.575. [DOI] [PubMed] [Google Scholar]
  18. Koide Y., Takasugi M. Determination of specificity in natural cell-mediated cytotoxicity by natural antibodies. J Natl Cancer Inst. 1977 Oct;59(4):1099–1105. doi: 10.1093/jnci/59.4.1099. [DOI] [PubMed] [Google Scholar]
  19. Minato N., Reid L., Cantor H., Lengyel P., Bloom B. R. Mode of regulation of natural killer cell activity by interferon. J Exp Med. 1980 Jul 1;152(1):124–137. doi: 10.1084/jem.152.1.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Oehler J. R., Herberman R. B. Natural cell-mediated cytotoxicity in rats. III. Effects of immunopharmacologic treatments on natural reactivity and on reactivity augmented by polyinosinic-polycytidylic acid. Int J Cancer. 1978 Feb 15;21(2):221–229. doi: 10.1002/ijc.2910210214. [DOI] [PubMed] [Google Scholar]
  21. Peter H. H., Pavie-Fischer J., Fridman W. H., Aubert C., Cesarini J. P., Roubin R., Kourilsky F. M. Cell-mediate cytotoxicity in vitro of human lymphocytes against a tissue culture melanoma cell line (igr3). J Immunol. 1975 Aug;115(2):539–548. [PubMed] [Google Scholar]
  22. Phillips J. H., Babcock G. F., Nishioka K. Tuftsin: a naturally occurring immunopotentiating factor. I. In vitro enhancement of murine natural cell-mediated cytotoxicity. J Immunol. 1981 Mar;126(3):915–921. [PubMed] [Google Scholar]
  23. Reynolds C. W., Herberman R. B. In vitro augmentation of rat natural killer (NK) cell activity. J Immunol. 1981 Apr;126(4):1581–1585. [PubMed] [Google Scholar]
  24. Roder J. C., Kiessling R., Biberfeld P., Andersson B. Target-effector interaction in the natural killer (NK) cell system. II. The isolation of NK cells and studies on the mechanism of killing. J Immunol. 1978 Dec;121(6):2509–2517. [PubMed] [Google Scholar]
  25. Santoli D., Koprowski H. Mechanisms of activation of human natural killer cells against tumor and virus-infected cells. Immunol Rev. 1979;44:125–163. doi: 10.1111/j.1600-065x.1979.tb00269.x. [DOI] [PubMed] [Google Scholar]
  26. Senik A., Gresser I., Maury C., Gidlund M., Orn A., Wigzell H. Enhancement by interferon of natural killer cell activity in mice. Cell Immunol. 1979 Apr;44(1):186–200. doi: 10.1016/0008-8749(79)90039-x. [DOI] [PubMed] [Google Scholar]
  27. Takasugi M., Mickey M. R., Terasaki P. I. Reactivity of lymphocytes from normal persons on cultured tumor cells. Cancer Res. 1973 Nov;33(11):2898–2902. [PubMed] [Google Scholar]
  28. Trinchieri G., De Marchi M. Antibody-dependent cell-mediated cytotoxicity in humans. III. Effect of protease inhibitors and substrates. J Immunol. 1976 Apr;116(4):885–891. [PubMed] [Google Scholar]
  29. Trinchieri G., Santoli D., Dee R. R., Knowles B. B. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Identification of the anti-viral activity as interferon and characterization of the human effector lymphocyte subpopulation. J Exp Med. 1978 May 1;147(5):1299–1313. doi: 10.1084/jem.147.5.1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Trinchieri G., Santoli D., Knowles B. B. Tumour cell lines induce interferon in human lymphocytes. Nature. 1977 Dec 15;270(5638):611–613. doi: 10.1038/270611a0. [DOI] [PubMed] [Google Scholar]
  31. Welsh R. M., Jr Mouse natural killer cells: induction specificity, and function. J Immunol. 1978 Nov;121(5):1631–1635. [PubMed] [Google Scholar]
  32. West W. H., Cannon G. B., Kay H. D., Bonnard G. D., Herberman R. B. Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells. J Immunol. 1977 Jan;118(1):355–361. [PubMed] [Google Scholar]
  33. Wolfe S. A., Tracey D. E., Henney C. S. Introduction of "natural" killer' cells by BCG. Nature. 1976 Aug 12;262(5569):584–586. doi: 10.1038/262584a0. [DOI] [PubMed] [Google Scholar]
  34. Zarling J. M., Eskra L., Borden E. C., Horoszewicz J., Carter W. A. Activation of human natural killer cells cytotoxic for human leukemia cells by purified interferon. J Immunol. 1979 Jul;123(1):63–70. [PubMed] [Google Scholar]

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