Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1997 Sep 29;352(1359):1311–1315. doi: 10.1098/rstb.1997.0115

Cytokines and nitric oxide as effector molecules against parasitic infections.

F Y Liew 1, X Q Wei 1, L Proudfoot 1
PMCID: PMC1692019  PMID: 9355122

Abstract

Nitric oxide (NO) derived from L-arginine by the catalytic action of inducible NO synthase (iNOS) plays an important role in killing parasites. Many cell types express high levels of iNOS when activated by a number of immunological stimuli which include interferon-gamma (IFN-gamma), tumour necrosis factor alpha, and lipopolysaccharide. IFN-gamma is typically produced by the Th1 subject of CD4+ T cells, whose differentiation depends on interleukin-12 (IL-12) produced by macrophages. Mice with a disrupted iNOS gene were highly susceptible to Leishmania major infection compared with similarly infected control wild-type mice. The mutant mice developed significantly higher levels of TH1-cell response compared with the control mice, suggesting that NO is likely to be the effector molecule in the immunological control of this and other intracellular parasitic infections. To ensure their survival, the Leishmania parasites have evolved effective means to inhibit NO synthesis. The highly conserved major surface glycolipids, glycoinositol-phospholipids and lipophosphoglycan (LPG), of Leishmania are potent inhibitors of NO synthesis. Furthermore, LPG can also inhibit IL-12 synthesis, thereby indirectly blocking the induction of iNOS. The evolutionary and therapeutic implications of these findings are discussed.

Full Text

The Full Text of this article is available as a PDF (110.6 KB).

Selected References

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

  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. Anthony L. S., Morrissey P. J., Nano F. E. Growth inhibition of Francisella tularensis live vaccine strain by IFN-gamma-activated macrophages is mediated by reactive nitrogen intermediates derived from L-arginine metabolism. J Immunol. 1992 Mar 15;148(6):1829–1834. [PubMed] [Google Scholar]
  4. Beckerman K. P., Rogers H. W., Corbett J. A., Schreiber R. D., McDaniel M. L., Unanue E. R. Release of nitric oxide during the T cell-independent pathway of macrophage activation. Its role in resistance to Listeria monocytogenes. J Immunol. 1993 Feb 1;150(3):888–895. [PubMed] [Google Scholar]
  5. Boockvar K. S., Granger D. L., Poston R. M., Maybodi M., Washington M. K., Hibbs J. B., Jr, Kurlander R. L. Nitric oxide produced during murine listeriosis is protective. Infect Immun. 1994 Mar;62(3):1089–1100. doi: 10.1128/iai.62.3.1089-1100.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bredt D. S., Snyder S. H. Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem. 1994;63:175–195. doi: 10.1146/annurev.bi.63.070194.001135. [DOI] [PubMed] [Google Scholar]
  7. Chan J., Tanaka K., Carroll D., Flynn J., Bloom B. R. Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. Infect Immun. 1995 Feb;63(2):736–740. doi: 10.1128/iai.63.2.736-740.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Feng H. M., Popov V. L., Walker D. H. Depletion of gamma interferon and tumor necrosis factor alpha in mice with Rickettsia conorii-infected endothelium: impairment of rickettsicidal nitric oxide production resulting in fatal, overwhelming rickettsial disease. Infect Immun. 1994 May;62(5):1952–1960. doi: 10.1128/iai.62.5.1952-1960.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feng H. M., Walker D. H. Interferon-gamma and tumor necrosis factor-alpha exert their antirickettsial effect via induction of synthesis of nitric oxide. Am J Pathol. 1993 Oct;143(4):1016–1023. [PMC free article] [PubMed] [Google Scholar]
  11. Fischer-Stenger K., Marciano-Cabral F. The arginine-dependent cytolytic mechanism plays a role in destruction of Naegleria fowleri amoebae by activated macrophages. Infect Immun. 1992 Dec;60(12):5126–5131. doi: 10.1128/iai.60.12.5126-5131.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Fortier A. H., Polsinelli T., Green S. J., Nacy C. A. Activation of macrophages for destruction of Francisella tularensis: identification of cytokines, effector cells, and effector molecules. Infect Immun. 1992 Mar;60(3):817–825. doi: 10.1128/iai.60.3.817-825.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gazzinelli R. T., Oswald I. P., Hieny S., James S. L., Sher A. The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. Eur J Immunol. 1992 Oct;22(10):2501–2506. doi: 10.1002/eji.1830221006. [DOI] [PubMed] [Google Scholar]
  15. Granger D. L., Hibbs J. B., Jr, Perfect J. R., Durack D. T. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J Clin Invest. 1988 Apr;81(4):1129–1136. doi: 10.1172/JCI113427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. James S. L., Glaven J. Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J Immunol. 1989 Dec 15;143(12):4208–4212. [PubMed] [Google Scholar]
  19. Kaplan S. S., Lancaster J. R., Jr, Basford R. E., Simmons R. L. Effect of nitric oxide on staphylococcal killing and interactive effect with superoxide. Infect Immun. 1996 Jan;64(1):69–76. doi: 10.1128/iai.64.1.69-76.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lee S. C., Dickson D. W., Brosnan C. F., Casadevall A. Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism. J Exp Med. 1994 Jul 1;180(1):365–369. doi: 10.1084/jem.180.1.365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Leitch G. J., He Q. Arginine-derived nitric oxide reduces fecal oocyst shedding in nude mice infected with Cryptosporidium parvum. Infect Immun. 1994 Nov;62(11):5173–5176. doi: 10.1128/iai.62.11.5173-5176.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Lin J. Y., Chadee K. Macrophage cytotoxicity against Entamoeba histolytica trophozoites is mediated by nitric oxide from L-arginine. J Immunol. 1992 Jun 15;148(12):3999–4005. [PubMed] [Google Scholar]
  24. MacMicking J. D., Nathan C., Hom G., Chartrain N., Fletcher D. S., Trumbauer M., Stevens K., Xie Q. W., Sokol K., Hutchinson N. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995 May 19;81(4):641–650. doi: 10.1016/0092-8674(95)90085-3. [DOI] [PubMed] [Google Scholar]
  25. Malawista S. E., Montgomery R. R., van Blaricom G. Evidence for reactive nitrogen intermediates in killing of staphylococci by human neutrophil cytoplasts. A new microbicidal pathway for polymorphonuclear leukocytes. J Clin Invest. 1992 Aug;90(2):631–636. doi: 10.1172/JCI115903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Marletta M. A. Nitric oxide synthase: aspects concerning structure and catalysis. Cell. 1994 Sep 23;78(6):927–930. doi: 10.1016/0092-8674(94)90268-2. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Modolell M., Schaible U. E., Rittig M., Simon M. M. Killing of Borrelia burgdorferi by macrophages is dependent on oxygen radicals and nitric oxide and can be enhanced by antibodies to outer surface proteins of the spirochete. Immunol Lett. 1994 May;40(2):139–146. doi: 10.1016/0165-2478(94)90185-6. [DOI] [PubMed] [Google Scholar]
  29. Moncada S., Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. doi: 10.1056/NEJM199312303292706. [DOI] [PubMed] [Google Scholar]
  30. Nathan C., Xie Q. W. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994 Sep 23;78(6):915–918. doi: 10.1016/0092-8674(94)90266-6. [DOI] [PubMed] [Google Scholar]
  31. Nussler A. K., Rénia L., Pasquetto V., Miltgen F., Matile H., Mazier D. In vivo induction of the nitric oxide pathway in hepatocytes after injection with irradiated malaria sporozoites, malaria blood parasites or adjuvants. Eur J Immunol. 1993 Apr;23(4):882–887. doi: 10.1002/eji.1830230417. [DOI] [PubMed] [Google Scholar]
  32. Nüssler A., Drapier J. C., Rénia L., Pied S., Miltgen F., Gentilini M., Mazier D. L-arginine-dependent destruction of intrahepatic malaria parasites in response to tumor necrosis factor and/or interleukin 6 stimulation. Eur J Immunol. 1991 Jan;21(1):227–230. doi: 10.1002/eji.1830210134. [DOI] [PubMed] [Google Scholar]
  33. Proudfoot L., Nikolaev A. V., Feng G. J., Wei W. Q., Ferguson M. A., Brimacombe J. S., Liew F. Y. Regulation of the expression of nitric oxide synthase and leishmanicidal activity by glycoconjugates of Leishmania lipophosphoglycan in murine macrophages. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10984–10989. doi: 10.1073/pnas.93.20.10984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Proudfoot L., O'Donnell C. A., Liew F. Y. Glycoinositolphospholipids of Leishmania major inhibit nitric oxide synthesis and reduce leishmanicidal activity in murine macrophages. Eur J Immunol. 1995 Mar;25(3):745–750. doi: 10.1002/eji.1830250318. [DOI] [PubMed] [Google Scholar]
  35. Rockett K. A., Awburn M. M., Cowden W. B., Clark I. A. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun. 1991 Sep;59(9):3280–3283. doi: 10.1128/iai.59.9.3280-3283.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Taylor-Robinson A. W., Phillips R. S., Severn A., Moncada S., Liew F. Y. The role of TH1 and TH2 cells in a rodent malaria infection. Science. 1993 Jun 25;260(5116):1931–1934. doi: 10.1126/science.8100366. [DOI] [PubMed] [Google Scholar]
  38. Turco J., Winkler H. H. 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. Infect Immun. 1993 Oct;61(10):4317–4325. doi: 10.1128/iai.61.10.4317-4325.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vazquez-Torres A., Jones-Carson J., Warner T., Balish E. Nitric oxide enhances resistance of SCID mice to mucosal candidiasis. J Infect Dis. 1995 Jul;172(1):192–198. doi: 10.1093/infdis/172.1.192. [DOI] [PubMed] [Google Scholar]
  40. Vespa G. N., Cunha F. Q., Silva J. S. Nitric oxide is involved in control of Trypanosoma cruzi-induced parasitemia and directly kills the parasite in vitro. Infect Immun. 1994 Nov;62(11):5177–5182. doi: 10.1128/iai.62.11.5177-5182.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vincendeau P., Daulouède S. Macrophage cytostatic effect on Trypanosoma musculi involves an L-arginine-dependent mechanism. J Immunol. 1991 Jun 15;146(12):4338–4343. [PubMed] [Google Scholar]
  42. Wei X. Q., Charles I. G., Smith A., Ure J., Feng G. J., Huang F. P., Xu D., Muller W., Moncada S., Liew F. Y. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature. 1995 Jun 1;375(6530):408–411. doi: 10.1038/375408a0. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES