Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1983 Oct;72(4):1506–1510. doi: 10.1172/JCI111107

Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-gamma is the activating lymphokine.

H W Murray, B Y Rubin, C D Rothermel
PMCID: PMC370435  PMID: 6415111

Abstract

We have found that the crude lymphokines, which prime the human monocyte-derived macrophage to generate H2O2 and exert microbicidal activity against intracellular Leishmania donovani, are rich in interferon (IFN)-gamma (600-3,000 U/ml). To determine the role of this specific lymphocyte product in macrophage activation, lymphokines were pretreated with a monoclonal antibody that neutralizes human IFN-gamma. Antibody exposure completely abolished the capacity of both mitogen- and antigen-stimulated lymphokines to either enhance macrophage H2O2 release or induce leishmanicidal activity. In addition, partially purified and pure recombinant human IFN-gamma were as effective as crude lymphokines in activating macrophages, and 3 d of treatment with 300 U/ml resulted in a seven- to eightfold increase in H2O2 generation and the intracellular killing of both L. donovani promastigotes and amastigotes. The ability of crude lymphokines to induce monocytes and macrophages from a patient with chronic granulomatous disease to kill L. donovani promastigotes was similarly abrogated by anti-IFN-gamma antibody, and could also be achieved by IFN-gamma alone. These results suggest that IFN-gamma is the key macrophage-activating molecule present within human lymphokines, and indicate that IFN-gamma can enhance both the oxygen-dependent and -independent antiprotozoal mechanisms of human mononuclear phagocytes.

Full text

PDF
1506

Selected References

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

  1. Anderson S. E., Bautista S., Remington J. S. Induction of resistance to Toxoplasma gondii in human macrophages by soluble lymphocyte products. J Immunol. 1976 Aug;117(2):381–387. [PubMed] [Google Scholar]
  2. Borges J. S., Johnson W. D., Jr Inhibition of multiplication of Toxoplasma gondii by human monocytes exposed to T-lymphocyte products. J Exp Med. 1975 Feb 1;141(2):483–496. doi: 10.1084/jem.141.2.483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carvalho E. M., Teixeira R. S., Johnson W. D., Jr Cell-mediated immunity in American visceral leishmaniasis: reversible immunosuppression during acute infection. Infect Immun. 1981 Aug;33(2):498–500. doi: 10.1128/iai.33.2.498-500.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gray P. W., Leung D. W., Pennica D., Yelverton E., Najarian R., Simonsen C. C., Derynck R., Sherwood P. J., Wallace D. M., Berger S. L. Expression of human immune interferon cDNA in E. coli and monkey cells. Nature. 1982 Feb 11;295(5849):503–508. doi: 10.1038/295503a0. [DOI] [PubMed] [Google Scholar]
  5. Kasahara T., Hooks J. J., Dougherty S. F., Oppenheim J. J. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 1983 Apr;130(4):1784–1789. [PubMed] [Google Scholar]
  6. Kazar J., Krautwurst P. A., Gordon F. B. Effect of Interferon and Interferon Inducers on Infections with a Nonviral Intracellular Microorganism, Rickettsia akari. Infect Immun. 1971 Jun;3(6):819–824. doi: 10.1128/iai.3.6.819-824.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Mizunoe K., Hiraki M., Nagano Y., Maehara N. Suppression of intracellular multiplication of Mycobacterium tuberculosis by virus-inhibiting factor or interferon. Jpn J Microbiol. 1975 Jun;19(3):235–236. doi: 10.1111/j.1348-0421.1975.tb00875.x. [DOI] [PubMed] [Google Scholar]
  8. Murray H. W., Byrne G. I., Rothermel C. D., Cartelli D. M. Lymphokine enhances oxygen-independent activity against intracellular pathogens. J Exp Med. 1983 Jul 1;158(1):234–239. doi: 10.1084/jem.158.1.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Murray H. W., Cartelli D. M. Killing of intracellular Leishmania donovani by human mononuclear phagocytes. Evidence for oxygen-dependent and -independent leishmanicidal activity. J Clin Invest. 1983 Jul;72(1):32–44. doi: 10.1172/JCI110972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Murray H. W., Masur H., Keithly J. S. Cell-mediated immune response in experimental visceral leishmaniasis. I. Correlation between resistance to Leishmania donovani and lymphokine-generating capacity. J Immunol. 1982 Jul;129(1):344–350. [PubMed] [Google Scholar]
  11. Nakagawara A., DeSantis N. M., Nogueira N., Nathan C. F. Lymphokines enhance the capacity of human monocytes to secret reactive oxygen intermediates. J Clin Invest. 1982 Nov;70(5):1042–1048. doi: 10.1172/JCI110691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Nogueira N., Chaplan S., Reesink M., Tydings J., Cohn Z. A. Trypanosoma cruzi: induction of microbicidal activity in human mononuclear phagocytes. J Immunol. 1982 May;128(5):2142–2146. [PubMed] [Google Scholar]
  13. Remington J. S., Merigan T. C. Interferon: protection of cells infected with an intracellular protozoan (Toxoplasma gondii). Science. 1968 Aug 23;161(3843):804–806. doi: 10.1126/science.161.3843.804. [DOI] [PubMed] [Google Scholar]
  14. Rubin B. Y., Bartal A. H., Anderson S. L., Millet S. K., Hirshaut Y., Feit C. The anticellular and protein-inducing activities of human gamma interferon preparations are mediated by the interferon. J Immunol. 1983 Mar;130(3):1019–1020. [PubMed] [Google Scholar]
  15. Sakurai H., Takei Y., Omata Y., Suzuki N. Production and properties of Toxoplasma growth inhibitory factor (Toxo-GIF) and interferon (IFN) in the lymphokines and the circulation of Toxoplasma immune mice. Zentralbl Bakteriol Mikrobiol Hyg A. 1981 Dec;251(1):134–143. [PubMed] [Google Scholar]
  16. Shirahata T., Shimizu K. Production and properties of immune interferon from spleen cell cultures of Toxoplasma-infected mice. Microbiol Immunol. 1980;24(11):1109–1120. doi: 10.1111/j.1348-0421.1980.tb02915.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES