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. 1996 Jun;64(6):1961–1967. doi: 10.1128/iai.64.6.1961-1967.1996

Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes.

J C Aliberti 1, M A Cardoso 1, G A Martins 1, R T Gazzinelli 1, L Q Vieira 1, J S Silva 1
PMCID: PMC174023  PMID: 8675294

Abstract

Host resistance to infection by Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the first week of infection in mice, NK cell-derived gamma interferon (IFN-gamma) is involved in controlling intracellular parasite replication, mainly through the induction of NO biosynthesis by activated macrophages. Interleukin-12 (IL-12) has been shown to be a powerful cytokine in inducing IFN-gamma synthesis by NK cells, as well as in mediating resistance to different intracellular protozoa. We have therefore studied the ability of T. cruzi to elicit IL-12 synthesis by macrophages and the role of this cytokine in controlling parasite replication during acute infection in mice. Our results show that macrophages cultured in the presence of live trypomastigote forms (but not epimastigotes) release IL-12 that can induce IFN-gamma production by normal spleen cells. IL-12 was detected in as little as 12 h after the addition of the trypomastigotes, and the level of IL-12 peaked at 48 h after the initial macrophage-parasite incubation. The addition of anti-IL-12 monoclonal antibody to macrophage-trypomastigote supernatants dose-dependently inhibited IFN-gamma production by naive splenocytes. Finally, the in vivo role of IL-12 in resistance to infection by T. cruzi was analyzed. Mice treated with anti-IL-12 monoclonal antibody had significantly increased parasitemia and mortality in comparison with those of control infected mice treated with control antibody. Together, these results suggest that macrophage-derived IL-12 plays a major role in controlling the parasitemia in T. cruzi-infected mice and that the animal's resistance during the acute phase of infection may, at least in part, be a consequence of postinfection levels of IL-12.

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Selected References

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  1. Biron C. A., Gazzinelli R. T. Effects of IL-12 on immune responses to microbial infections: a key mediator in regulating disease outcome. Curr Opin Immunol. 1995 Aug;7(4):485–496. doi: 10.1016/0952-7915(95)80093-x. [DOI] [PubMed] [Google Scholar]
  2. Cardillo F., Voltarelli J. C., Reed S. G., Silva J. S. Regulation of Trypanosoma cruzi infection in mice by gamma interferon and interleukin 10: role of NK cells. Infect Immun. 1996 Jan;64(1):128–134. doi: 10.1128/iai.64.1.128-134.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. GOBLE F. C., BOYD J. L. Reticulo-endothelial blockade in experimental Chagas' disease. J Parasitol. 1962 Apr;48:223–228. [PubMed] [Google Scholar]
  5. Gately M. K., Warrier R. R., Honasoge S., Carvajal D. M., Faherty D. A., Connaughton S. E., Anderson T. D., Sarmiento U., Hubbard B. R., Murphy M. Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. Int Immunol. 1994 Jan;6(1):157–167. doi: 10.1093/intimm/6.1.157. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Gazzinelli R. T., Wysocka M., Hayashi S., Denkers E. Y., Hieny S., Caspar P., Trinchieri G., Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed] [Google Scholar]
  8. Hunter C. A., Bermudez L., Beernink H., Waegell W., Remington J. S. Transforming growth factor-beta inhibits interleukin-12-induced production of interferon-gamma by natural killer cells: a role for transforming growth factor-beta in the regulation of T cell-independent resistance to Toxoplasma gondii. Eur J Immunol. 1995 Apr;25(4):994–1000. doi: 10.1002/eji.1830250420. [DOI] [PubMed] [Google Scholar]
  9. James S. L., Kipnis T. L., Sher A., Hoff R. Enhanced resistance to acute infection with Trypanosoma cruzi in mice treated with an interferon inducer. Infect Immun. 1982 Feb;35(2):588–593. doi: 10.1128/iai.35.2.588-593.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Krettli A. U., Brener Z. Protective effects of specific antibodies in Trypanosoma cruzi infections. J Immunol. 1976 Mar;116(3):755–760. [PubMed] [Google Scholar]
  12. Mattner F., Fischer S., Guckes S., Jin S., Kaulen H., Schmitt E., Rüde E., Germann T. The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer. Eur J Immunol. 1993 Sep;23(9):2202–2208. doi: 10.1002/eji.1830230923. [DOI] [PubMed] [Google Scholar]
  13. Melo R. C., Brener Z. Tissue tropism of different Trypanosoma cruzi strains. J Parasitol. 1978 Jun;64(3):475–482. [PubMed] [Google Scholar]
  14. Nathan C. F., Hibbs J. B., Jr Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991 Feb;3(1):65–70. doi: 10.1016/0952-7915(91)90079-g. [DOI] [PubMed] [Google Scholar]
  15. Nathan C., Nogueira N., Juangbhanich C., Ellis J., Cohn Z. Activation of macrophages in vivo and in vitro. Correlation between hydrogen peroxide release and killing of Trypanosoma cruzi. J Exp Med. 1979 May 1;149(5):1056–1068. doi: 10.1084/jem.149.5.1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nogueira N., Cohn Z. A. Trypanosoma cruzi: in vitro induction of macrophage microbicidal activity. J Exp Med. 1978 Jul 1;148(1):288–300. doi: 10.1084/jem.148.1.288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Orange J. S., Wolf S. F., Biron C. A. Effects of IL-12 on the response and susceptibility to experimental viral infections. J Immunol. 1994 Feb 1;152(3):1253–1264. [PubMed] [Google Scholar]
  18. Reed S. G. In vivo administration of recombinant IFN-gamma induces macrophage activation, and prevents acute disease, immune suppression, and death in experimental Trypanosoma cruzi infections. J Immunol. 1988 Jun 15;140(12):4342–4347. [PubMed] [Google Scholar]
  19. Reiner S. L., Zheng S., Wang Z. E., Stowring L., Locksley R. M. Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection. J Exp Med. 1994 Feb 1;179(2):447–456. doi: 10.1084/jem.179.2.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rottenberg M., Cardoni R. L., Andersson R., Segura E. L., Orn A. Role of T helper/inducer cells as well as natural killer cells in resistance to Trypanosoma cruzi infection. Scand J Immunol. 1988 Nov;28(5):573–582. doi: 10.1111/j.1365-3083.1988.tb01489.x. [DOI] [PubMed] [Google Scholar]
  21. Russo M., Starobinas N., Minoprio P., Coutinho A., Hontebeyrie-Joskowicz M. Parasitic load increases and myocardial inflammation decreases in Trypanosoma cruzi-infected mice after inactivation of helper T cells. Ann Inst Pasteur Immunol. 1988 May-Jun;139(3):225–236. doi: 10.1016/0769-2625(88)90136-5. [DOI] [PubMed] [Google Scholar]
  22. Sher A., Oswald I. P., Hieny S., Gazzinelli R. T. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha. J Immunol. 1993 May 1;150(9):3982–3989. [PubMed] [Google Scholar]
  23. Silva J. S., Morrissey P. J., Grabstein K. H., Mohler K. M., Anderson D., Reed S. G. Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection. J Exp Med. 1992 Jan 1;175(1):169–174. doi: 10.1084/jem.175.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Silva J. S., Twardzik D. R., Reed S. G. Regulation of Trypanosoma cruzi infections in vitro and in vivo by transforming growth factor beta (TGF-beta). J Exp Med. 1991 Sep 1;174(3):539–545. doi: 10.1084/jem.174.3.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Silva J. S., Vespa G. N., Cardoso M. A., Aliberti J. C., Cunha F. Q. Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages. Infect Immun. 1995 Dec;63(12):4862–4867. doi: 10.1128/iai.63.12.4862-4867.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Stern A. S., Podlaski F. J., Hulmes J. D., Pan Y. C., Quinn P. M., Wolitzky A. G., Familletti P. C., Stremlo D. L., Truitt T., Chizzonite R. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. doi: 10.1073/pnas.87.17.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tarleton R. L. Depletion of CD8+ T cells increases susceptibility and reverses vaccine-induced immunity in mice infected with Trypanosoma cruzi. J Immunol. 1990 Jan 15;144(2):717–724. [PubMed] [Google Scholar]
  28. Tarleton R. L., Koller B. H., Latour A., Postan M. Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature. 1992 Mar 26;356(6367):338–340. doi: 10.1038/356338a0. [DOI] [PubMed] [Google Scholar]
  29. Torrico F., Heremans H., Rivera M. T., Van Marck E., Billiau A., Carlier Y. Endogenous IFN-gamma is required for resistance to acute Trypanosoma cruzi infection in mice. J Immunol. 1991 May 15;146(10):3626–3632. [PubMed] [Google Scholar]
  30. Tripp C. S., Gately M. K., Hakimi J., Ling P., Unanue E. R. Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. Reversal by IFN-gamma. J Immunol. 1994 Feb 15;152(4):1883–1887. [PubMed] [Google Scholar]
  31. Tripp C. S., Wolf S. F., Unanue E. R. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. doi: 10.1073/pnas.90.8.3725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tsunawaki S., Sporn M., Ding A., Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988 Jul 21;334(6179):260–262. doi: 10.1038/334260a0. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Vieira L. Q., Hondowicz B. D., Afonso L. C., Wysocka M., Trinchieri G., Scott P. Infection with Leishmania major induces interleukin-12 production in vivo. Immunol Lett. 1994 May;40(2):157–161. doi: 10.1016/0165-2478(94)90187-2. [DOI] [PubMed] [Google Scholar]

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