Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1993 Oct;61(10):4317–4325. doi: 10.1128/iai.61.10.4317-4325.1993

Role of the nitric oxide synthase pathway in inhibition of growth of interferon-sensitive and interferon-resistant Rickettsia prowazekii strains in L929 cells treated with tumor necrosis factor alpha and gamma interferon.

J Turco 1, H H Winkler 1
PMCID: PMC281160  PMID: 7691748

Abstract

The ability of tumor necrosis factor alpha (TNF-alpha) alone and in combination with gamma interferon (IFN-gamma) to inhibit the growth of interferon-sensitive and -resistant Rickettsia prowazekii strains in mouse L929 cells was examined, and the possible role of the nitric oxide synthase pathway in the suppression of rickettsial growth induced by TNF-alpha, IFN-gamma, or both cytokines was evaluated. TNF-alpha inhibited the growth of strains Madrid E (IFN-gamma sensitive and alpha/beta interferon [IFN-alpha/beta] sensitive) and Breinl (IFN-gamma sensitive and IFN-alpha/beta resistant), but not that of strain 83-2P (IFN-gamma resistant and IFN-alpha/beta resistant), in L929 cells. Inhibition of the growth of the Madrid E strain in L929 cells treated with TNF-alpha and IFN-gamma in combination was greater than that observed with either TNF-alpha or IFN-gamma alone. Similarly, inhibition of the growth of the Breinl strain in L929 cells treated with both cytokines was greater than that observed with TNF-alpha alone; however, it did not differ significantly from the inhibition observed with IFN-gamma alone. Although strain 83-2P was resistant to TNF-alpha or IFN-gamma alone, its growth was inhibited in L929 cells treated with TNF-alpha and IFN-gamma in combination. Nitrite production was measured in mock-infected and infected L929 cell cultures, and the nitric oxide synthase inhibitors NG-methyl-L-arginine (NGMA) and aminoguanidine were used to evaluate the role of the nitric oxide synthase pathway in cytokine-induced inhibition of rickettsial growth. Nitrite production was induced in mock-infected or R. prowazekii-infected L929 cell cultures treated with IFN-gamma plus TNF-alpha, but not in mock-infected cultures that were untreated or treated with IFN-gamma or TNF-alpha alone. Nitrite production was also not induced in untreated, R. prowazekii-infected cultures; however, in some instances, it was induced in infected cultures treated with IFN-gamma or TNF-alpha alone. Nitrite production was blocked by NGMA or aminoguanidine, and these compounds markedly relieved the synergistic inhibitory effect of IFN-gamma plus TNF-alpha on the growth of strain 83-2P in L929 cells. In contrast, NGMA did not alleviate the inhibition of the growth of the Madrid E strain in L929 cells treated with IFN-gamma or TNF-alpha alone; however, it slightly and variably relieved the inhibition of the growth of the Madrid E strain in L929 cells treated with IFN-gamma and TNF-alpha in combination.(ABSTRACT TRUNCATED AT 400 WORDS)

Full text

PDF
4317

Selected References

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

  1. Amber I. J., Hibbs J. B., Jr, Taintor R. R., Vavrin Z. Cytokines induce an L-arginine-dependent effector system in nonmacrophage cells. J Leukoc Biol. 1988 Jul;44(1):58–65. doi: 10.1002/jlb.44.1.58. [DOI] [PubMed] [Google Scholar]
  2. BOVARNICK M. R., MILLER J. C., SNYDER J. C. The influence of certain salts, amino acids, sugars, and proteins on the stability of rickettsiae. J Bacteriol. 1950 Apr;59(4):509–522. doi: 10.1128/jb.59.4.509-522.1950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beresini M. H., Lempert M. J., Epstein L. B. Overlapping polypeptide induction in human fibroblasts in response to treatment with interferon-alpha, interferon-gamma, interleukin 1 alpha, interleukin 1 beta, and tumor necrosis factor. J Immunol. 1988 Jan 15;140(2):485–493. [PubMed] [Google Scholar]
  4. Beresini M. H., Sugarman B. J., Shepard H. M., Epstein L. B. Synergistic induction of polypeptides by tumor necrosis factor and interferon-gamma in cells sensitive or resistant to tumor necrosis factor: assessment by computer based analysis of two-dimensional gels using the PDQUEST system. Electrophoresis. 1990 Mar;11(3):232–241. doi: 10.1002/elps.1150110307. [DOI] [PubMed] [Google Scholar]
  5. Byrne G. I., Lehmann L. K., Landry G. J. Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun. 1986 Aug;53(2):347–351. doi: 10.1128/iai.53.2.347-351.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Fast D. J., Lynch R. C., Leu R. W. Nitric oxide production by tumor targets in response to TNF: paradoxical correlation with susceptibility to TNF-mediated cytotoxicity without direct involvement in the cytotoxic mechanism. J Leukoc Biol. 1992 Sep;52(3):255–261. doi: 10.1002/jlb.52.3.255. [DOI] [PubMed] [Google Scholar]
  9. Feduchi E., Carrasco L. Mechanism of inhibition of HSV-1 replication by tumor necrosis factor and interferon gamma. Virology. 1991 Feb;180(2):822–825. doi: 10.1016/0042-6822(91)90100-p. [DOI] [PubMed] [Google Scholar]
  10. GIMENEZ D. F. STAINING RICKETTSIAE IN YOLK-SAC CULTURES. Stain Technol. 1964 May;39:135–140. doi: 10.3109/10520296409061219. [DOI] [PubMed] [Google Scholar]
  11. Green S. J., Meltzer M. S., Hibbs J. B., Jr, Nacy C. A. Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol. 1990 Jan 1;144(1):278–283. [PubMed] [Google Scholar]
  12. Hanson B. Comparative susceptibility to mouse interferons of Rickettsia tsutsugamushi strains with different virulence in mice and of Rickettsia rickettsii. Infect Immun. 1991 Nov;59(11):4134–4141. doi: 10.1128/iai.59.11.4134-4141.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Havell E. A. Production of tumor necrosis factor during murine listeriosis. J Immunol. 1987 Dec 15;139(12):4225–4231. [PubMed] [Google Scholar]
  14. Hibbs J. B., Jr, Taintor R. R., Vavrin Z., Rachlin E. M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. doi: 10.1016/s0006-291x(88)80015-9. [DOI] [PubMed] [Google Scholar]
  15. Hughes T. K., Baron S. A large component of the antiviral activity of mouse interferon-gamma may be due to its induction of interferon-alpha. J Biol Regul Homeost Agents. 1987 Jan-Mar;1(1):29–32. [PubMed] [Google Scholar]
  16. Hughes T. K., Baron S. Do the interferons act singly or in combination? J Interferon Res. 1987 Oct;7(5):603–614. doi: 10.1089/jir.1987.7.603. [DOI] [PubMed] [Google Scholar]
  17. Jacobsen H., Mestan J., Mittnacht S., Dieffenbach C. W. Beta interferon subtype 1 induction by tumor necrosis factor. Mol Cell Biol. 1989 Jul;9(7):3037–3042. doi: 10.1128/mcb.9.7.3037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Li H., Jerrells T. R., Spitalny G. L., Walker D. H. Gamma interferon as a crucial host defense against Rickettsia conorii in vivo. Infect Immun. 1987 May;55(5):1252–1255. doi: 10.1128/iai.55.5.1252-1255.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Marletta M. A., Yoon P. S., Iyengar R., Leaf C. D., Wishnok J. S. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry. 1988 Nov 29;27(24):8706–8711. doi: 10.1021/bi00424a003. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Misko T. P., Moore W. M., Kasten T. P., Nickols G. A., Corbett J. A., Tilton R. G., McDaniel M. L., Williamson J. R., Currie M. G. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993 Mar 16;233(1):119–125. doi: 10.1016/0014-2999(93)90357-n. [DOI] [PubMed] [Google Scholar]
  24. Nussler A. K., Di Silvio M., Billiar T. R., Hoffman R. A., Geller D. A., Selby R., Madariaga J., Simmons R. L. Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med. 1992 Jul 1;176(1):261–264. doi: 10.1084/jem.176.1.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pfefferkorn E. R. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc Natl Acad Sci U S A. 1984 Feb;81(3):908–912. doi: 10.1073/pnas.81.3.908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reis L. F., Ho Lee T., Vilcek J. Tumor necrosis factor acts synergistically with autocrine interferon-beta and increases interferon-beta mRNA levels in human fibroblasts. J Biol Chem. 1989 Oct 5;264(28):16351–16354. [PubMed] [Google Scholar]
  27. Rubin B. Y., Anderson S. L., Lunn R. M., Richardson N. K., Hellermann G. R., Smith L. J., Old L. J. Tumor necrosis factor and IFN induce a common set of proteins. J Immunol. 1988 Aug 15;141(4):1180–1184. [PubMed] [Google Scholar]
  28. Shemer-Avni Y., Wallach D., Sarov I. Reversion of the antichlamydial effect of tumor necrosis factor by tryptophan and antibodies to beta interferon. Infect Immun. 1989 Nov;57(11):3484–3490. doi: 10.1128/iai.57.11.3484-3490.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Stamler J. S., Singel D. J., Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. 1992 Dec 18;258(5090):1898–1902. doi: 10.1126/science.1281928. [DOI] [PubMed] [Google Scholar]
  30. Stuehr D. J., Gross S. S., Sakuma I., Levi R., Nathan C. F. Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J Exp Med. 1989 Mar 1;169(3):1011–1020. doi: 10.1084/jem.169.3.1011. [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. Comparison of properties of virulent, avirulent, and interferon-resistant Rickettsia prowazekii strains. Infect Immun. 1991 May;59(5):1647–1655. doi: 10.1128/iai.59.5.1647-1655.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Turco J., Winkler H. H. Comparison of the properties of antirickettsial activity and interferon in mouse lymphokines. Infect Immun. 1983 Oct;42(1):27–32. doi: 10.1128/iai.42.1.27-32.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Turco J., Winkler H. H. Effect of mouse lymphokines and cloned mouse interferon-gamma on the interaction of Rickettsia prowazekii with mouse macrophage-like RAW264.7 cells. Infect Immun. 1984 Aug;45(2):303–308. doi: 10.1128/iai.45.2.303-308.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Turco J., Winkler H. H. Gamma-interferon-induced inhibition of the growth of Rickettsia prowazekii in fibroblasts cannot be explained by the degradation of tryptophan or other amino acids. Infect Immun. 1986 Jul;53(1):38–46. doi: 10.1128/iai.53.1.38-46.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Turco J., Winkler H. H. Interferon-alpha/beta and Rickettsia prowazekii: induction and sensitivity. Ann N Y Acad Sci. 1990;590:168–186. doi: 10.1111/j.1749-6632.1990.tb42219.x. [DOI] [PubMed] [Google Scholar]
  40. Turco J., Winkler H. H. Isolation of Rickettsia prowazekii with reduced sensitivity to gamma interferon. Infect Immun. 1989 Jun;57(6):1765–1772. doi: 10.1128/iai.57.6.1765-1772.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Turco J., Winkler H. H. Selection of alpha/beta interferon- and gamma interferon-resistant rickettsiae by passage of Rickettsia prowazekii in L929 cells. Infect Immun. 1990 Oct;58(10):3279–3285. doi: 10.1128/iai.58.10.3279-3285.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Walker T. S., Winkler H. H. Rickettsial hemolysis: rapid method for enumeration of metabolically active typhus rickettsiae. J Clin Microbiol. 1979 May;9(5):645–647. doi: 10.1128/jcm.9.5.645-647.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Weil J., Epstein C. J., Epstein L. B., Sedmak J. J., Sabran J. L., Grossberg S. E. A unique set of polypeptides is induced by gamma interferon in addition to those induced in common with alpha and beta interferons. Nature. 1983 Feb 3;301(5899):437–439. doi: 10.1038/301437a0. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. 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]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES