Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1996 Aug;64(8):3429–3434. doi: 10.1128/iai.64.8.3429-3434.1996

Granulocyte-macrophage colony-stimulating factor: involvement in control of Trypanosoma cruzi infection in mice.

E Olivares Fontt 1, C Heirman 1, K Thielemans 1, B Vray 1
PMCID: PMC174243  PMID: 8757888

Abstract

Several cytokines play crucial roles in Trypanosoma cruzi infection in mice, but the involvement of endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) is poorly documented. This report shows that T. cruzi infection of mice triggered an early and sharp increase in plasma GM-CSF during the ascending phase of parasitemia. The plasma GM-CSF concentration remained stable at the peak of parasitemia and subsequently increased in those mice that survived to the acute phase. GM-CSF level increased again sharply, while parasitemia was rapidly decreasing. Finally, GM-CSF was undetectable, soon after the disappearance of circulating parasites. Injection of T. cruzi-infected mice with neutralizing anti-GM-CSF monoclonal antibodies induced the early appearance of parasitemia and aggravated cumulative mortality. In contrast, recombinant mouse GM-CSF (rmGM-CSF) caused sharp decreases in both parasitemia and cumulative mortality in T. cruzi-infected mice. Peritoneal macrophages from rmGM-CSF-treated and infected or uninfected mice were less infected ex vivo than those from control mice. Taken together these data demonstrate the protective action of endogenous GM-CSF in T. cruzi infection. Neutralization of endogenous GM-CSF aggravates infection, while exogenous rmGM-CSF decreases both parasitemia and host mortality.

Full Text

The Full Text of this article is available as a PDF (231.3 KB).

Selected References

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

  1. Abrahamsohn I. A., Coffman R. L. Cytokine and nitric oxide regulation of the immunosuppression in Trypanosoma cruzi infection. J Immunol. 1995 Oct 15;155(8):3955–3963. [PubMed] [Google Scholar]
  2. BRENER Z. Therapeutic activity and criterion of cure on mice experimentally infected with Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo. 1962 Nov-Dec;4:389–396. [PubMed] [Google Scholar]
  3. Badaró R., Nascimento C., Carvalho J. S., Badaró F., Russo D., Ho J. L., Reed S. G., Johnson W. D., Jr, Jones T. C. Recombinant human granulocyte-macrophage colony-stimulating factor reverses neutropenia and reduces secondary infections in visceral leishmaniasis. J Infect Dis. 1994 Aug;170(2):413–418. doi: 10.1093/infdis/170.2.413. [DOI] [PubMed] [Google Scholar]
  4. Bermudez L. E., Young L. S. Recombinant granulocyte-macrophage colony-stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex. J Leukoc Biol. 1990 Jul;48(1):67–73. doi: 10.1002/jlb.48.1.67. [DOI] [PubMed] [Google Scholar]
  5. Bilyk N., Holt P. G. Inhibition of the immunosuppressive activity of resident pulmonary alveolar macrophages by granulocyte/macrophage colony-stimulating factor. J Exp Med. 1993 Jun 1;177(6):1773–1777. doi: 10.1084/jem.177.6.1773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coleman D. L., Chodakewitz J. A., Bartiss A. H., Mellors J. W. Granulocyte-macrophage colony-stimulating factor enhances selective effector functions of tissue-derived macrophages. Blood. 1988 Aug;72(2):573–578. [PubMed] [Google Scholar]
  7. Denis M. Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J Leukoc Biol. 1991 Apr;49(4):380–387. doi: 10.1002/jlb.49.4.380. [DOI] [PubMed] [Google Scholar]
  8. Fischer H. G., Frosch S., Reske K., Reske-Kunz A. B. Granulocyte-macrophage colony-stimulating factor activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augmented antigen presentation function. J Immunol. 1988 Dec 1;141(11):3882–3888. [PubMed] [Google Scholar]
  9. Gasson J. C. Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood. 1991 Mar 15;77(6):1131–1145. [PubMed] [Google Scholar]
  10. 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]
  11. Grabstein K. H., Urdal D. L., Tushinski R. J., Mochizuki D. Y., Price V. L., Cantrell M. A., Gillis S., Conlon P. J. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factor. Science. 1986 Apr 25;232(4749):506–508. doi: 10.1126/science.3083507. [DOI] [PubMed] [Google Scholar]
  12. Hamilton J. A. Colony stimulating factors, cytokines and monocyte-macrophages--some controversies. Immunol Today. 1993 Jan;14(1):18–24. doi: 10.1016/0167-5699(93)90319-G. [DOI] [PubMed] [Google Scholar]
  13. Hamilton J. A., Whitty G. A., Royston A. K., Cebon J., Layton J. E. Interleukin-4 suppresses granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in stimulated human monocytes. Immunology. 1992 Aug;76(4):566–571. [PMC free article] [PubMed] [Google Scholar]
  14. Hayes M. M., Kierszenbaum F. Experimental Chagas' disease: kinetics of lymphocyte responses and immunological control of the transition from acute to chronic Trypanosoma cruzi infection. Infect Immun. 1981 Mar;31(3):1117–1124. doi: 10.1128/iai.31.3.1117-1124.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hoft D. F., Lynch R. G., Kirchhoff L. V. Kinetic analysis of antigen-specific immune responses in resistant and susceptible mice during infection with Trypanosoma cruzi. J Immunol. 1993 Dec 15;151(12):7038–7047. [PubMed] [Google Scholar]
  16. Kaushansky K., Broudy V. C., Harlan J. M., Adamson J. W. Tumor necrosis factor-alpha and tumor necrosis factor-beta (lymphotoxin) stimulate the production of granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in vivo. J Immunol. 1988 Nov 15;141(10):3410–3415. [PubMed] [Google Scholar]
  17. Magee D. M., Wing E. J. Secretion of colony-stimulating factors by T cell clones. Role in adoptive protection against Listeria monocytogenes. J Immunol. 1989 Oct 1;143(7):2336–2341. [PubMed] [Google Scholar]
  18. Metcalf D., Elliott M. J., Nicola N. A. The excess numbers of peritoneal macrophages in granulocyte-macrophage colony-stimulating factor transgenic mice are generated by local proliferation. J Exp Med. 1992 Apr 1;175(4):877–884. doi: 10.1084/jem.175.4.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Morrissey P. J., Bressler L., Park L. S., Alpert A., Gillis S. Granulocyte-macrophage colony-stimulating factor augments the primary antibody response by enhancing the function of antigen-presenting cells. J Immunol. 1987 Aug 15;139(4):1113–1119. [PubMed] [Google Scholar]
  20. Muñoz-Fernández M. A., Fernández M. A., Fresno M. Synergism between tumor necrosis factor-alpha and interferon-gamma on macrophage activation for the killing of intracellular Trypanosoma cruzi through a nitric oxide-dependent mechanism. Eur J Immunol. 1992 Feb;22(2):301–307. doi: 10.1002/eji.1830220203. [DOI] [PubMed] [Google Scholar]
  21. Nabors G. S., Tarleton R. L. Differential control of IFN-gamma and IL-2 production during Trypanosoma cruzi infection. J Immunol. 1991 May 15;146(10):3591–3598. [PubMed] [Google Scholar]
  22. Olivares Fontt E., Vray B. Relationship between granulocyte macrophage-colony stimulating factor, tumour necrosis factor-alpha and Trypanosoma cruzi infection of murine macrophages. Parasite Immunol. 1995 Mar;17(3):135–141. doi: 10.1111/j.1365-3024.1995.tb01015.x. [DOI] [PubMed] [Google Scholar]
  23. Plasman N., Guillet J. G., Vray B. Impaired protein catabolism in Trypanosoma cruzi-infected macrophages: possible involvement in antigen presentation. Immunology. 1995 Dec;86(4):636–645. [PMC free article] [PubMed] [Google Scholar]
  24. Reed S. G., Grabstein K. H., Pihl D. L., Morrissey P. J. Recombinant granulocyte-macrophage colony-stimulating factor restores deficient immune responses in mice with chronic Trypanosoma cruzi infections. J Immunol. 1990 Sep 1;145(5):1564–1570. [PubMed] [Google Scholar]
  25. Reed S. G., Nathan C. F., Pihl D. L., Rodricks P., Shanebeck K., Conlon P. J., Grabstein K. H. Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide. Comparison with interferon gamma. J Exp Med. 1987 Dec 1;166(6):1734–1746. doi: 10.1084/jem.166.6.1734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rottenberg M. E., Sunnemark D., Leandersson T., Orn A. Organ-specific regulation of interferon-gamma, interleukin-2 and interleukin-2 receptor during murine infection with Trypanosoma cruzi. Scand J Immunol. 1993 May;37(5):559–568. doi: 10.1111/j.1365-3083.1993.tb02572.x. [DOI] [PubMed] [Google Scholar]
  27. Sato N., Sawada K., Tarumi T., Koizumi K., Yasukouchi T., Takahashi T. A., Sekiguchi S., Koike T. Recombinant human interleukin-4 inhibits the production of granulocyte-macrophage colony stimulating factor by blood mononuclear cells. Br J Haematol. 1994 Apr;86(4):695–701. doi: 10.1111/j.1365-2141.1994.tb04817.x. [DOI] [PubMed] [Google Scholar]
  28. Schreck R., Baeuerle P. A. NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene. Mol Cell Biol. 1990 Mar;10(3):1281–1286. doi: 10.1128/mcb.10.3.1281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Spinella S., Liegeard P., Hontebeyrie-Joskowicz M. Trypanosoma cruzi: predominance of IgG2a in nonspecific humoral response during experimental Chagas' disease. Exp Parasitol. 1992 Feb;74(1):46–56. doi: 10.1016/0014-4894(92)90138-z. [DOI] [PubMed] [Google Scholar]
  32. Tanowitz H. B., Kirchhoff L. V., Simon D., Morris S. A., Weiss L. M., Wittner M. Chagas' disease. Clin Microbiol Rev. 1992 Oct;5(4):400–419. doi: 10.1128/cmr.5.4.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tarleton R. L. Regulation of immunity in Trypanosoma cruzi infection. Exp Parasitol. 1991 Jul;73(1):106–109. doi: 10.1016/0014-4894(91)90013-m. [DOI] [PubMed] [Google Scholar]
  34. Tarleton R. L. Tumour necrosis factor (cachectin) production during experimental Chagas' disease. Clin Exp Immunol. 1988 Aug;73(2):186–190. [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Truyens C., Angelo-Barrios A., Torrico F., Van Damme J., Heremans H., Carlier Y. Interleukin-6 (IL-6) production in mice infected with Trypanosoma cruzi: effect of its paradoxical increase by anti-IL-6 monoclonal antibody treatment on infection and acute-phase and humoral immune responses. Infect Immun. 1994 Feb;62(2):692–696. doi: 10.1128/iai.62.2.692-696.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vray B., De Baetselier P., Ouaissi A., Carlier Y. Trypanosoma cruzi but not Trypanosoma brucei fails to induce a chemiluminescent signal in a macrophage hybridoma cell line. Infect Immun. 1991 Sep;59(9):3303–3308. doi: 10.1128/iai.59.9.3303-3308.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Williams D. E., Cooper S., Broxmeyer H. E. Effects of hematopoietic suppressor molecules on the in vitro proliferation of purified murine granulocyte-macrophage progenitor cells. Cancer Res. 1988 Mar 15;48(6):1548–1550. [PubMed] [Google Scholar]
  39. Zhang L., Tarleton R. L. Characterization of cytokine production in murine Trypanosoma cruzi infection by in situ immunocytochemistry: lack of association between susceptibility and type 2 cytokine production. Eur J Immunol. 1996 Jan;26(1):102–109. doi: 10.1002/eji.1830260116. [DOI] [PubMed] [Google Scholar]
  40. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES