Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Feb 1;183(2):515–526. doi: 10.1084/jem.183.2.515

Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice

PMCID: PMC2192469  PMID: 8627163

Abstract

Leishmania major promastigotes were found to avoid activation of mouse bone marrow-derived macrophages (BMM0) in vitro for production of cytokines that are typically induced during infection with other intracellular pathogens. Coexposure of BMM0 to the parasite and other microbial stimuli resulted in complete inhibition of interleukin (IL) 12 (p40) mRNA induction and IL-12 release. In contrast, mRNA and protein levels for IL-1(alpha), IL-1(beta), tumor necrosis factor (TNF) alpha, and inducible NO synthase (iNOS) were only partially reduced, and signals for IL-10 and monocyte chemoattractant protein (MCP-1/JE) were enhanced. The parasite could provide a detectable trigger for TNF- alpha and iNOS in BMM0 primed with interferon (IFN) gamma, but still failed to induce IL-12. Thus IL-12 induction is selectively impaired after infection, whereas activation pathways for other monokine responses remain relatively intact. Selective and complete inhibition of IL-12(p40) induction was observed using BMM0 from either genetically susceptible or resistant mouse strains, as well as IL-10 knockout mice, and was obtained using promastigotes from cutaneous, visceral, and lipophosphoglycan-deficient strains of Leishmania. The impaired production of the major physiological inducer of IFN-gamma is suggested to underlie the relatively prolonged interval of parasite intracellular survival and replication that is typically associate with leishmanial infections, including those producing self-limiting disease.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

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

  1. Afonso L. C., Scharton T. M., Vieira L. Q., Wysocka M., Trinchieri G., Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994 Jan 14;263(5144):235–237. doi: 10.1126/science.7904381. [DOI] [PubMed] [Google Scholar]
  2. Bancroft G. J., Schreiber R. D., Unanue E. R. Natural immunity: a T-cell-independent pathway of macrophage activation, defined in the scid mouse. Immunol Rev. 1991 Dec;124:5–24. doi: 10.1111/j.1600-065x.1991.tb00613.x. [DOI] [PubMed] [Google Scholar]
  3. Barral-Netto M., Barral A., Brownell C. E., Skeiky Y. A., Ellingsworth L. R., Twardzik D. R., Reed S. G. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science. 1992 Jul 24;257(5069):545–548. doi: 10.1126/science.1636092. [DOI] [PubMed] [Google Scholar]
  4. Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
  5. Bogdan C., Paik J., Vodovotz Y., Nathan C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem. 1992 Nov 15;267(32):23301–23308. [PubMed] [Google Scholar]
  6. Chakkalath H. R., Titus R. G. Leishmania major-parasitized macrophages augment Th2-type T cell activation. J Immunol. 1994 Nov 15;153(10):4378–4387. [PubMed] [Google Scholar]
  7. Cillari E., Dieli M., Maltese E., Milano S., Salerno A., Liew F. Y. Enhancement of macrophage IL-1 production by Leishmania major infection in vitro and its inhibition by IFN-gamma. J Immunol. 1989 Sep 15;143(6):2001–2005. [PubMed] [Google Scholar]
  8. Cooper A. M., Melby P. C., Karp C. L., Neva F., Sacks D. L. T-cell responses to infected autologous monocytes in patients with cutaneous and mucocutaneous leishmaniasis. Clin Diagn Lab Immunol. 1994 May;1(3):304–309. doi: 10.1128/cdli.1.3.304-309.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cooper A. M., Roberts A. D., Rhoades E. R., Callahan J. E., Getzy D. M., Orme I. M. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995 Mar;84(3):423–432. [PMC free article] [PubMed] [Google Scholar]
  10. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Descoteaux A., Matlashewski G., Turco S. J. Inhibition of macrophage protein kinase C-mediated protein phosphorylation by Leishmania donovani lipophosphoglycan. J Immunol. 1992 Nov 1;149(9):3008–3015. [PubMed] [Google Scholar]
  12. Descoteaux A., Turco S. J. The lipophosphoglycan of Leishmania and macrophage protein kinase C. Parasitol Today. 1993 Dec;9(12):468–471. doi: 10.1016/0169-4758(93)90105-o. [DOI] [PubMed] [Google Scholar]
  13. Ding L., Linsley P. S., Huang L. Y., Germain R. N., Shevach E. M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993 Aug 1;151(3):1224–1234. [PubMed] [Google Scholar]
  14. Doherty T. M., Coffman R. L. Leishmania antigens presented by GM-CSF-derived macrophages protect susceptible mice against challenge with Leishmania major. J Immunol. 1993 Jun 15;150(12):5476–5483. [PubMed] [Google Scholar]
  15. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
  17. Gajewski T. F., Pinnas M., Wong T., Fitch F. W. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations. J Immunol. 1991 Mar 15;146(6):1750–1758. [PubMed] [Google Scholar]
  18. Gazzinelli R. T., Eltoum I., Wynn T. A., Sher A. Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation. J Immunol. 1993 Oct 1;151(7):3672–3681. [PubMed] [Google Scholar]
  19. Gazzinelli R. T., Hieny S., Wynn T. A., Wolf S., Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. doi: 10.1073/pnas.90.13.6115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Ghalib H. W., Piuvezam M. R., Skeiky Y. A., Siddig M., Hashim F. A., el-Hassan A. M., Russo D. M., Reed S. G. Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest. 1993 Jul;92(1):324–329. doi: 10.1172/JCI116570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Heinzel F. P., Rerko R. M., Ahmed F., Pearlman E. Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. J Immunol. 1995 Jul 15;155(2):730–739. [PubMed] [Google Scholar]
  24. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hsieh C. S., Macatonia S. E., O'Garra A., Murphy K. M. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995 Feb 1;181(2):713–721. doi: 10.1084/jem.181.2.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  27. Karp C. L., el-Safi S. H., Wynn T. A., Satti M. M., Kordofani A. M., Hashim F. A., Hag-Ali M., Neva F. A., Nutman T. B., Sacks D. L. In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma. J Clin Invest. 1993 Apr;91(4):1644–1648. doi: 10.1172/JCI116372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kaye P. M., Coburn C., McCrossan M., Beverley S. M. Antigens targeted to the Leishmania phagolysosome are processed for CD4+ T cell recognition. Eur J Immunol. 1993 Sep;23(9):2311–2319. doi: 10.1002/eji.1830230939. [DOI] [PubMed] [Google Scholar]
  29. Kaye P. M., Rogers N. J., Curry A. J., Scott J. C. Deficient expression of co-stimulatory molecules on Leishmania-infected macrophages. Eur J Immunol. 1994 Nov;24(11):2850–2854. doi: 10.1002/eji.1830241140. [DOI] [PubMed] [Google Scholar]
  30. King D. L., Turco S. J. A ricin agglutinin-resistant clone of Leishmania donovani deficient in lipophosphoglycan. Mol Biochem Parasitol. 1988 Apr;28(3):285–293. doi: 10.1016/0166-6851(88)90013-8. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Kolesnick R., Golde D. W. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell. 1994 May 6;77(3):325–328. doi: 10.1016/0092-8674(94)90147-3. [DOI] [PubMed] [Google Scholar]
  33. Kubin M., Kamoun M., Trinchieri G. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med. 1994 Jul 1;180(1):211–222. doi: 10.1084/jem.180.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  35. Lang T., Hellio R., Kaye P. M., Antoine J. C. Leishmania donovani-infected macrophages: characterization of the parasitophorous vacuole and potential role of this organelle in antigen presentation. J Cell Sci. 1994 Aug;107(Pt 8):2137–2150. doi: 10.1242/jcs.107.8.2137. [DOI] [PubMed] [Google Scholar]
  36. McConville M. J., Ferguson M. A. The structure, biosynthesis and function of glycosylated phosphatidylinositols in the parasitic protozoa and higher eukaryotes. Biochem J. 1993 Sep 1;294(Pt 2):305–324. doi: 10.1042/bj2940305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Melby P. C. Experimental leishmaniasis in humans: review. Rev Infect Dis. 1991 Sep-Oct;13(5):1009–1017. doi: 10.1093/clinids/13.5.1009. [DOI] [PubMed] [Google Scholar]
  38. Moore K. J., Labrecque S., Matlashewski G. Alteration of Leishmania donovani infection levels by selective impairment of macrophage signal transduction. J Immunol. 1993 May 15;150(10):4457–4465. [PubMed] [Google Scholar]
  39. Moore K. J., Matlashewski G. Intracellular infection by Leishmania donovani inhibits macrophage apoptosis. J Immunol. 1994 Mar 15;152(6):2930–2937. [PubMed] [Google Scholar]
  40. Murphy E. E., Terres G., Macatonia S. E., Hsieh C. S., Mattson J., Lanier L., Wysocka M., Trinchieri G., Murphy K., O'Garra A. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med. 1994 Jul 1;180(1):223–231. doi: 10.1084/jem.180.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Murray H. W., Hariprashad J. Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis. J Exp Med. 1995 Jan 1;181(1):387–391. doi: 10.1084/jem.181.1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Murray H. W., Masur H., Keithly J. S. Cell-mediated immune response in experimental visceral leishmaniasis. I. Correlation between resistance to Leishmania donovani and lymphokine-generating capacity. J Immunol. 1982 Jul;129(1):344–350. [PubMed] [Google Scholar]
  43. Nelson B. J., Ralph P., Green S. J., Nacy C. A. Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1. J Immunol. 1991 Mar 15;146(6):1849–1857. [PubMed] [Google Scholar]
  44. Olivier M., Brownsey R. W., Reiner N. E. Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7481–7485. doi: 10.1073/pnas.89.16.7481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reed S. G., Scott P. T-cell and cytokine responses in leishmaniasis. Curr Opin Immunol. 1993 Aug;5(4):524–531. doi: 10.1016/0952-7915(93)90033-o. [DOI] [PubMed] [Google Scholar]
  46. Reiner N. E., Ng W., McMaster W. R. Parasite-accessory cell interactions in murine leishmaniasis. II. Leishmania donovani suppresses macrophage expression of class I and class II major histocompatibility complex gene products. J Immunol. 1987 Mar 15;138(6):1926–1932. [PubMed] [Google Scholar]
  47. Reiner N. E. Parasite accessory cell interactions in murine leishmaniasis. I. Evasion and stimulus-dependent suppression of the macrophage interleukin 1 response by Leishmania donovani. J Immunol. 1987 Mar 15;138(6):1919–1925. [PubMed] [Google Scholar]
  48. 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]
  49. Sacks D. L., Hieny S., Sher A. Identification of cell surface carbohydrate and antigenic changes between noninfective and infective developmental stages of Leishmania major promastigotes. J Immunol. 1985 Jul;135(1):564–569. [PubMed] [Google Scholar]
  50. Scharton-Kersten T., Afonso L. C., Wysocka M., Trinchieri G., Scott P. IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis. J Immunol. 1995 May 15;154(10):5320–5330. [PubMed] [Google Scholar]
  51. Scharton T. M., Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993 Aug 1;178(2):567–577. doi: 10.1084/jem.178.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Seder R. A., Gazzinelli R., Sher A., Paul W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. doi: 10.1073/pnas.90.21.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shapira L., Takashiba S., Champagne C., Amar S., Van Dyke T. E. Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. J Immunol. 1994 Aug 15;153(4):1818–1824. [PubMed] [Google Scholar]
  54. Svetić A., Finkelman F. D., Jian Y. C., Dieffenbach C. W., Scott D. E., McCarthy K. F., Steinberg A. D., Gause W. C. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J Immunol. 1991 Oct 1;147(7):2391–2397. [PubMed] [Google Scholar]
  55. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. 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]
  57. 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]
  58. 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]
  59. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]
  60. Wu C. Y., Demeure C., Kiniwa M., Gately M., Delespesse G. IL-12 induces the production of IFN-gamma by neonatal human CD4 T cells. J Immunol. 1993 Aug 15;151(4):1938–1949. [PubMed] [Google Scholar]
  61. Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]
  62. Yoshimura T., Yuhki N., Moore S. K., Appella E., Lerman M. I., Leonard E. J. Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE. FEBS Lett. 1989 Feb 27;244(2):487–493. doi: 10.1016/0014-5793(89)80590-3. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES