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. 1993 Oct;143(4):1016–1023.

Interferon-gamma and tumor necrosis factor-alpha exert their antirickettsial effect via induction of synthesis of nitric oxide.

H M Feng 1, D H Walker 1
PMCID: PMC1887061  PMID: 8213997

Abstract

How the host defenses control rickettsiae in the cytosol of nonphagocytic host cells, where they are not exposed to antibodies or phagocytes, has posed a difficult question. Rickettsia conorii infection of a mouse fibroblast cell line was inhibited in a dose-dependent manner by nitrogen oxide synthesized by eukaryotic host cells stimulated by interferon-gamma or tumor necrosis factor-alpha. L-arginine was the source of the nitric oxide as demonstrated by competitive inhibition by NG-monomethyl-L-arginine. Nitric oxide synthesis required host cell protein synthesis and had an approximately 48-hour lag phase following cytokine stimulation. At low doses of interferon-gamma and tumor necrosis factor-alpha, which had no detectable response as single agents, dramatic synergistic nitric oxide synthesis and antirickettsial effects were observed.

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Selected References

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  1. Adams L. B., Franzblau S. G., Vavrin Z., Hibbs J. B., Jr, Krahenbuhl J. L. L-arginine-dependent macrophage effector functions inhibit metabolic activity of Mycobacterium leprae. J Immunol. 1991 Sep 1;147(5):1642–1646. [PubMed] [Google Scholar]
  2. Adams L. B., Hibbs J. B., Jr, Taintor R. R., Krahenbuhl J. L. Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from L-arginine. J Immunol. 1990 Apr 1;144(7):2725–2729. [PubMed] [Google Scholar]
  3. Chan J., Xing Y., Magliozzo R. S., Bloom B. R. Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. J Exp Med. 1992 Apr 1;175(4):1111–1122. doi: 10.1084/jem.175.4.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Crist A. E., Jr, Wisseman C. L., Jr, Murphy J. R. Characteristics of lymphoid cells that adoptively transfer immunity to Rickettsia mooseri infection in mice. Infect Immun. 1984 Apr;44(1):55–60. doi: 10.1128/iai.44.1.55-60.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Denis M. Interferon-gamma-treated murine macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates. Cell Immunol. 1991 Jan;132(1):150–157. doi: 10.1016/0008-8749(91)90014-3. [DOI] [PubMed] [Google Scholar]
  6. Drapier J. C., Hibbs J. B., Jr Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol. 1988 Apr 15;140(8):2829–2838. [PubMed] [Google Scholar]
  7. Fausto N. What's in a Name? The American Society for Investigative Pathology. Am J Pathol. 1993 Jan;142(1):1–1. [PMC free article] [PubMed] [Google Scholar]
  8. Flesch I. E., Kaufmann S. H. Mechanisms involved in mycobacterial growth inhibition by gamma interferon-activated bone marrow macrophages: role of reactive nitrogen intermediates. Infect Immun. 1991 Sep;59(9):3213–3218. doi: 10.1128/iai.59.9.3213-3218.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Green S. J., Crawford R. M., Hockmeyer J. T., Meltzer M. S., Nacy C. A. Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha. J Immunol. 1990 Dec 15;145(12):4290–4297. [PubMed] [Google Scholar]
  10. Green S. J., Nacy C. A., Schreiber R. D., Granger D. L., Crawford R. M., Meltzer M. S., Fortier A. H. Neutralization of gamma interferon and tumor necrosis factor alpha blocks in vivo synthesis of nitrogen oxides from L-arginine and protection against Francisella tularensis infection in Mycobacterium bovis BCG-treated mice. Infect Immun. 1993 Feb;61(2):689–698. doi: 10.1128/iai.61.2.689-698.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herrero-Herrero J. I., Walker D. H., Ruiz-Beltran R. Immunohistochemical evaluation of the cellular immune response to Rickettsia conorii in taches noires. J Infect Dis. 1987 Apr;155(4):802–805. doi: 10.1093/infdis/155.4.802. [DOI] [PubMed] [Google Scholar]
  12. Higginbotham J. N., Lin T. L., Pruett S. B. Effect of macrophage activation on killing of Listeria monocytogenes. Roles of reactive oxygen or nitrogen intermediates, rate of phagocytosis, and retention of bacteria in endosomes. Clin Exp Immunol. 1992 Jun;88(3):492–498. doi: 10.1111/j.1365-2249.1992.tb06477.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jerrells T. R., Turco J., Winkler H. H., Spitalny G. L. Neutralization of lymphokine-mediated antirickettsial activity of fibroblasts and macrophages with monoclonal antibody specific for murine interferon gamma. Infect Immun. 1986 Jan;51(1):355–359. doi: 10.1128/iai.51.1.355-359.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kenyon R. H., Pedersen C. E., Jr Immune responses to Rickettsia akari infection in congenitally athymic nude mice. Infect Immun. 1980 May;28(2):310–313. doi: 10.1128/iai.28.2.310-313.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kilbourn R. G., Belloni P. Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst. 1990 May 2;82(9):772–776. doi: 10.1093/jnci/82.9.772. [DOI] [PubMed] [Google Scholar]
  16. Kokorin I. N., Kabanova E. A., Shirokova E. M., Abrosimova G. E., Rybkina N. N., Pushkareva V. i. Role of T lymphocytes in Rickettsia conorii infection. Acta Virol. 1982 Jan;26(1-2):91–97. [PubMed] [Google Scholar]
  17. Liew F. Y., Li Y., Millott S. Tumor necrosis factor-alpha synergizes with IFN-gamma in mediating killing of Leishmania major through the induction of nitric oxide. J Immunol. 1990 Dec 15;145(12):4306–4310. [PubMed] [Google Scholar]
  18. Liew F. Y., Millott S., Parkinson C., Palmer R. M., Moncada S. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol. 1990 Jun 15;144(12):4794–4797. [PubMed] [Google Scholar]
  19. Manor E., Sarov I. Inhibition of Rickettsia conorii growth by recombinant tumor necrosis factor alpha: enhancement of inhibition by gamma interferon. Infect Immun. 1990 Jun;58(6):1886–1890. doi: 10.1128/iai.58.6.1886-1890.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Manor E., Sarov I. Tumor necrosis factor alpha and prostaglandin E2 production by human monocyte-derived macrophages infected with spotted fever group rickettsiae. Ann N Y Acad Sci. 1990;590:157–167. doi: 10.1111/j.1749-6632.1990.tb42218.x. [DOI] [PubMed] [Google Scholar]
  21. Mayer J., Woods M. L., Vavrin Z., Hibbs J. B., Jr Gamma interferon-induced nitric oxide production reduces Chlamydia trachomatis infectivity in McCoy cells. Infect Immun. 1993 Feb;61(2):491–497. doi: 10.1128/iai.61.2.491-497.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Moe J. B., Mosher D. F., Kenyon R. H., White J. D., Stookey J. L., Bagley L. R., Fine D. P. Functional and morphologic changes during experimental Rocky Mountain spotted fever in guinea pigs. Lab Invest. 1976 Sep;35(3):235–245. [PubMed] [Google Scholar]
  23. Montenegro N. R., Walker D. H., Hegarty B. C. Infection of genetically immunodeficient mice with Rickettsia conorii. Acta Virol. 1984 Nov;28(6):508–514. [PubMed] [Google Scholar]
  24. Mülsch A., Bassenge E., Busse R. Nitric oxide synthesis in endothelial cytosol: evidence for a calcium-dependent and a calcium-independent mechanism. Naunyn Schmiedebergs Arch Pharmacol. 1989 Dec;340(6 Pt 2):767–770. doi: 10.1007/BF00169688. [DOI] [PubMed] [Google Scholar]
  25. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  26. Park J., Rikihisa Y. L-arginine-dependent killing of intracellular Ehrlichia risticii by macrophages treated with gamma interferon. Infect Immun. 1992 Sep;60(9):3504–3508. doi: 10.1128/iai.60.9.3504-3508.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pellat C., Henry Y., Drapier J. C. IFN-gamma-activated macrophages: detection by electron paramagnetic resonance of complexes between L-arginine-derived nitric oxide and non-heme iron proteins. Biochem Biophys Res Commun. 1990 Jan 15;166(1):119–125. doi: 10.1016/0006-291x(90)91919-j. [DOI] [PubMed] [Google Scholar]
  28. Radomski M. W., Palmer R. M., Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun. 1987 Nov 13;148(3):1482–1489. doi: 10.1016/s0006-291x(87)80299-1. [DOI] [PubMed] [Google Scholar]
  29. Salvemini D., Pistelli A., Mollace V., Anggård E., Vane J. The metabolism of glyceryl trinitrate to nitric oxide in the macrophage cell line J774 and its induction by Escherichia coli lipopolysaccharide. Biochem Pharmacol. 1992 Jul 7;44(1):17–24. doi: 10.1016/0006-2952(92)90032-e. [DOI] [PubMed] [Google Scholar]
  30. Santucci L. A., Gutierrez P. L., Silverman D. J. Rickettsia rickettsii induces superoxide radical and superoxide dismutase in human endothelial cells. Infect Immun. 1992 Dec;60(12):5113–5118. doi: 10.1128/iai.60.12.5113-5118.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Summersgill J. T., Powell L. A., Buster B. L., Miller R. D., Ramirez J. A. Killing of Legionella pneumophila by nitric oxide in gamma-interferon-activated macrophages. J Leukoc Biol. 1992 Dec;52(6):625–629. doi: 10.1002/jlb.52.6.625. [DOI] [PubMed] [Google Scholar]
  33. Turco J., Winkler H. H. Cloned mouse interferon-gamma inhibits the growth of Rickettsia prowazekii in cultured mouse fibroblasts. J Exp Med. 1983 Dec 1;158(6):2159–2164. doi: 10.1084/jem.158.6.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Turco J., Winkler H. H. Inhibition of the growth of Rickettsia prowazekii in cultured fibroblasts by lymphokines. J Exp Med. 1983 Mar 1;157(3):974–986. doi: 10.1084/jem.157.3.974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Walker D. H., Gear J. H. Correlation of the distribution of Rickettsia conorii, microscopic lesions, and clinical features in South African tick bite fever. Am J Trop Med Hyg. 1985 Mar;34(2):361–371. doi: 10.4269/ajtmh.1985.34.361. [DOI] [PubMed] [Google Scholar]
  36. Walker D. H., Parks F. M., Betz T. G., Taylor J. P., Muehlberger J. W. Histopathology and immunohistologic demonstration of the distribution of Rickettsia typhi in fatal murine typhus. Am J Clin Pathol. 1989 Jun;91(6):720–724. doi: 10.1093/ajcp/91.6.720. [DOI] [PubMed] [Google Scholar]
  37. Werner-Felmayer G., Werner E. R., Fuchs D., Hausen A., Reibnegger G., Wachter H. Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts. J Exp Med. 1990 Dec 1;172(6):1599–1607. doi: 10.1084/jem.172.6.1599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wisseman C. L., Jr, Waddell A. Interferonlike factors from antigen- and mitogen-stimulated human leukocytes with antirickettsial and cytolytic actions on Rickettsia prowazekii. Infected human endothelial cells, fibroblasts, and macrophages. J Exp Med. 1983 Jun 1;157(6):1780–1793. doi: 10.1084/jem.157.6.1780. [DOI] [PMC free article] [PubMed] [Google Scholar]

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