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J Exp Med. 1996 February 1; 183(2): 515–526.
PMCID: PMC2192469

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


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.

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Selected References

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  • Murray HW, Masur H, Keithly JS. 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]
  • Belosevic M, Finbloom DS, Van Der Meide PH, Slayter MV, Nacy CA. 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]
  • Reed SG, Scott P. T-cell and cytokine responses in leishmaniasis. Curr Opin Immunol. 1993 Aug;5(4):524–531. [PubMed]
  • Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, 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. [PMC free article] [PubMed]
  • Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM, et al. 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]
  • Seder RA, Gazzinelli R, Sher A, Paul WE. 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. [PubMed]
  • Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. [PMC free article] [PubMed]
  • Sypek JP, Chung CL, Mayor SE, Subramanyam JM, Goldman SJ, Sieburth DS, Wolf SF, Schaub RG. 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. [PMC free article] [PubMed]
  • Afonso LC, Scharton TM, Vieira LQ, 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. [PubMed]
  • Murray HW, 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. [PMC free article] [PubMed]
  • Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. [PubMed]
  • Tripp CS, Wolf SF, Unanue ER. 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. [PubMed]
  • Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, 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]
  • Cooper AM, Roberts AD, Rhoades ER, Callahan JE, Getzy DM, Orme IM. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995 Mar;84(3):423–432. [PubMed]
  • Reiner SL, Zheng S, Wang ZE, Stowring L, Locksley RM. 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. [PMC free article] [PubMed]
  • Hsieh CS, Macatonia SE, O'Garra A, Murphy KM. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995 Feb 1;181(2):713–721. [PMC free article] [PubMed]
  • Vieira LQ, Hondowicz BD, Afonso LC, Wysocka M, Trinchieri G, Scott P. Infection with Leishmania major induces interleukin-12 production in vivo. Immunol Lett. 1994 May;40(2):157–161. [PubMed]
  • 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. [PubMed]
  • Descoteaux A, Matlashewski G, Turco SJ. Inhibition of macrophage protein kinase C-mediated protein phosphorylation by Leishmania donovani lipophosphoglycan. J Immunol. 1992 Nov 1;149(9):3008–3015. [PubMed]
  • King DL, Turco SJ. A ricin agglutinin-resistant clone of Leishmania donovani deficient in lipophosphoglycan. Mol Biochem Parasitol. 1988 Apr;28(3):285–293. [PubMed]
  • Sacks DL, 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]
  • Gazzinelli RT, Eltoum I, Wynn TA, 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]
  • Wynn TA, Eltoum I, Cheever AW, Lewis FA, Gause WC, 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]
  • Svetić A, Finkelman FD, Jian YC, Dieffenbach CW, Scott DE, McCarthy KF, Steinberg AD, Gause WC. 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]
  • Gazzinelli RT, Hieny S, Wynn TA, 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. [PubMed]
  • Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ. 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. [PubMed]
  • Chakkalath HR, Titus RG. Leishmania major-parasitized macrophages augment Th2-type T cell activation. J Immunol. 1994 Nov 15;153(10):4378–4387. [PubMed]
  • Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA. 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]
  • Fiorentino DF, Bond MW, Mosmann TR. 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. [PMC free article] [PubMed]
  • Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed]
  • D'Andrea A, Aste-Amezaga M, Valiante NM, 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. [PMC free article] [PubMed]
  • Descoteaux A, Turco SJ. The lipophosphoglycan of Leishmania and macrophage protein kinase C. Parasitol Today. 1993 Dec;9(12):468–471. [PubMed]
  • Kaye PM, Coburn C, McCrossan M, Beverley SM. Antigens targeted to the Leishmania phagolysosome are processed for CD4+ T cell recognition. Eur J Immunol. 1993 Sep;23(9):2311–2319. [PubMed]
  • Lang T, Hellio R, Kaye PM, Antoine JC. 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. [PubMed]
  • Cooper AM, Melby PC, Karp CL, Neva F, Sacks DL. T-cell responses to infected autologous monocytes in patients with cutaneous and mucocutaneous leishmaniasis. Clin Diagn Lab Immunol. 1994 May;1(3):304–309. [PMC free article] [PubMed]
  • Shapira L, Takashiba S, Champagne C, Amar S, Van Dyke TE. 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]
  • Kolesnick R, Golde DW. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell. 1994 May 6;77(3):325–328. [PubMed]
  • Cillari E, Dieli M, Maltese E, Milano S, Salerno A, Liew FY. 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]
  • Moore KJ, Matlashewski G. Intracellular infection by Leishmania donovani inhibits macrophage apoptosis. J Immunol. 1994 Mar 15;152(6):2930–2937. [PubMed]
  • Reiner NE. 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]
  • Reiner NE, Ng W, McMaster WR. 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]
  • Melby PC. Experimental leishmaniasis in humans: review. Rev Infect Dis. 1991 Sep-Oct;13(5):1009–1017. [PubMed]
  • Bancroft GJ, Schreiber RD, Unanue ER. Natural immunity: a T-cell-independent pathway of macrophage activation, defined in the scid mouse. Immunol Rev. 1991 Dec;124:5–24. [PubMed]
  • Heinzel FP, Rerko RM, 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]
  • Scharton TM, 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. [PMC free article] [PubMed]
  • Scharton-Kersten T, Afonso LC, 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]
  • Doherty TM, Coffman RL. 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]
  • Gajewski TF, Pinnas M, Wong T, Fitch FW. 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]
  • Ding L, Linsley PS, Huang LY, Germain RN, Shevach EM. 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]
  • Kaye PM, Rogers NJ, Curry AJ, Scott JC. Deficient expression of co-stimulatory molecules on Leishmania-infected macrophages. Eur J Immunol. 1994 Nov;24(11):2850–2854. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Murphy EE, Terres G, Macatonia SE, Hsieh CS, 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. [PMC free article] [PubMed]
  • Karp CL, el-Safi SH, Wynn TA, Satti MM, Kordofani AM, Hashim FA, Hag-Ali M, Neva FA, Nutman TB, Sacks DL. 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. [PMC free article] [PubMed]
  • Ghalib HW, Piuvezam MR, Skeiky YA, Siddig M, Hashim FA, el-Hassan AM, Russo DM, Reed SG. Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest. 1993 Jul;92(1):324–329. [PMC free article] [PubMed]
  • Nelson BJ, Ralph P, Green SJ, Nacy CA. 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]
  • Barral-Netto M, Barral A, Brownell CE, Skeiky YA, Ellingsworth LR, Twardzik DR, Reed SG. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science. 1992 Jul 24;257(5069):545–548. [PubMed]
  • Tsunawaki S, Sporn M, Ding A, Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988 Jul 21;334(6179):260–262. [PubMed]
  • Wu CY, 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]
  • 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]
  • Moore KJ, 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]
  • Olivier M, Brownsey RW, Reiner NE. 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. [PubMed]
  • McConville MJ, Ferguson MA. 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. [PubMed]

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