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. 1990 Jun;85(6):1914–1924. doi: 10.1172/JCI114654

Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1.

N E Reiner 1, W Ng 1, C B Wilson 1, W R McMaster 1, S K Burchett 1
PMCID: PMC296659  PMID: 2112157

Abstract

Cytokines produced by mononuclear cells are important regulatory and effector molecules and evidence has been presented to support a role at least for tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in host defense against Leishmania. In the present study, we examined the production of TNF-alpha and interleukin 1 (IL-1) by resting and IFN-gamma-primed peripheral blood monocytes infected in vitro with Leishmania donovani. Monocytes produced neither IL-1 nor TNF-alpha during challenge with Leishmania. Cells preinfected with Leishmania synthesized normal amounts of TNF-alpha, but had diminished production of IL-1 in response to stimulation with either S. aureus or lipopolysaccharide (LPS). The induction by S. aureus or LPS of IL-1 beta mRNA accumulation in infected cells was normal despite diminished intracellular or supernatant IL-1 protein and bioactivity. Thus, inhibition of IL-1 production by Leishmania most probably reflected diminished translation of IL-1 beta mRNA. Pretreatment of cells with IFN-gamma abrogated infection-induced inhibition of IL-1 production and primed cells for the production of both IL-1 and TNF-alpha upon subsequent exposure to Leishmania. These results indicate that L. donovani has evolved the capacity to infect mononuclear phagocytes, without stimulating the production of two potentially host-protective monokines. The ability of IFN-gamma to prime monocytes to produce TNF-alpha and IL-1 in response to infection with Leishmania and to prevent inhibition of IL-1 production may have implications for immunotherapy with this lymphokine.

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Selected References

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

  1. Arend W. P., Joslin F. G., Massoni R. J. Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol. 1985 Jun;134(6):3868–3875. [PubMed] [Google Scholar]
  2. Arenzana-Seisdedos F., Virelizier J. L., Fiers W. Interferons as macrophage-activating factors. III. Preferential effects of interferon-gamma on the interleukin 1 secretory potential of fresh or aged human monocytes. J Immunol. 1985 Apr;134(4):2444–2448. [PubMed] [Google Scholar]
  3. Badaro R., Falcoff E., Badaro F. S., Carvalho E. M., Pedral-Sampaio D., Barral A., Carvalho J. S., Barral-Netto M., Brandely M., Silva L. Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. N Engl J Med. 1990 Jan 4;322(1):16–21. doi: 10.1056/NEJM199001043220104. [DOI] [PubMed] [Google Scholar]
  4. Bermudez L. E., Young L. S. Tumor necrosis factor, alone or in combination with IL-2, but not IFN-gamma, is associated with macrophage killing of Mycobacterium avium complex. J Immunol. 1988 May 1;140(9):3006–3013. [PubMed] [Google Scholar]
  5. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  6. Boraschi D., Censini S., Bartalini M., Tagliabue A. Regulation of arachidonic acid metabolism in macrophages by immune and nonimmune interferons. J Immunol. 1985 Jul;135(1):502–505. [PubMed] [Google Scholar]
  7. Boraschi D., Censini S., Tagliabue A. Interferon-gamma reduces macrophage-suppressive activity by inhibiting prostaglandin E2 release and inducing interleukin 1 production. J Immunol. 1984 Aug;133(2):764–768. [PubMed] [Google Scholar]
  8. Browning J. L., Ribolini A. Interferon blocks interleukin 1-induced prostaglandin release from human peripheral monocytes. J Immunol. 1987 May 1;138(9):2857–2863. [PubMed] [Google Scholar]
  9. Burchett S. K., Weaver W. M., Westall J. A., Larsen A., Kronheim S., Wilson C. B. Regulation of tumor necrosis factor/cachectin and IL-1 secretion in human mononuclear phagocytes. J Immunol. 1988 May 15;140(10):3473–3481. [PubMed] [Google Scholar]
  10. Carvalho E. M., Andrews B. S., Martinelli R., Dutra M., Rocha H. Circulating immune complexes and rheumatoid factor in schistosomiasis and visceral leishmaniasis. Am J Trop Med Hyg. 1983 Jan;32(1):61–68. doi: 10.4269/ajtmh.1983.32.61. [DOI] [PubMed] [Google Scholar]
  11. Carvalho E. M., Badaró R., Reed S. G., Jones T. C., Johnson W. D., Jr Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Invest. 1985 Dec;76(6):2066–2069. doi: 10.1172/JCI112209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Crawford G. D., Wyler D. J., Dinarello C. A. Parasite-monocyte interactions in human leishmaniasis: production of interleukin-1 in vitro. J Infect Dis. 1985 Aug;152(2):315–322. doi: 10.1093/infdis/152.2.315. [DOI] [PubMed] [Google Scholar]
  15. Czuprynski C. J., Brown J. F., Young K. M., Cooley A. J., Kurtz R. S. Effects of murine recombinant interleukin 1 alpha on the host response to bacterial infection. J Immunol. 1988 Feb 1;140(3):962–968. [PubMed] [Google Scholar]
  16. De Titto E. H., Catterall J. R., Remington J. S. Activity of recombinant tumor necrosis factor on Toxoplasma gondii and Trypanosoma cruzi. J Immunol. 1986 Aug 15;137(4):1342–1345. [PubMed] [Google Scholar]
  17. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  18. Dinarello C. A., Bishai I., Rosenwasser L. J., Coceani F. The influence of lipoxygenase inhibitors on the in vitro production of human leukocytic pyrogen and lymphocyte activating factor (interleukin-1). Int J Immunopharmacol. 1984;6(1):43–50. doi: 10.1016/0192-0561(84)90033-x. [DOI] [PubMed] [Google Scholar]
  19. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dinarello C. A. Interleukin-1. Rev Infect Dis. 1984 Jan-Feb;6(1):51–95. doi: 10.1093/clinids/6.1.51. [DOI] [PubMed] [Google Scholar]
  21. Durum S. K., Schmidt J. A., Oppenheim J. J. Interleukin 1: an immunological perspective. Annu Rev Immunol. 1985;3:263–287. doi: 10.1146/annurev.iy.03.040185.001403. [DOI] [PubMed] [Google Scholar]
  22. Fenton M. J., Vermeulen M. W., Clark B. D., Webb A. C., Auron P. E. Human pro-IL-1 beta gene expression in monocytic cells is regulated by two distinct pathways. J Immunol. 1988 Apr 1;140(7):2267–2273. [PubMed] [Google Scholar]
  23. Gerrard T. L., Siegel J. P., Dyer D. R., Zoon K. C. Differential effects of interferon-alpha and interferon-gamma on interleukin 1 secretion by monocytes. J Immunol. 1987 Apr 15;138(8):2535–2540. [PubMed] [Google Scholar]
  24. Gray P. W., Glaister D., Chen E., Goeddel D. V., Pennica D. Two interleukin 1 genes in the mouse: cloning and expression of the cDNA for murine interleukin 1 beta. J Immunol. 1986 Dec 1;137(11):3644–3648. [PubMed] [Google Scholar]
  25. Haq A. U., Rinehart J. J., Maca R. D. The effect of gamma interferon on IL-1 secretion of in vitro differentiated human macrophages. J Leukoc Biol. 1985 Dec;38(6):735–746. doi: 10.1002/jlb.38.6.735. [DOI] [PubMed] [Google Scholar]
  26. Kaye J., Gillis S., Mizel S. B., Shevach E. M., Malek T. R., Dinarello C. A., Lachman L. B., Janeway C. A., Jr Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. J Immunol. 1984 Sep;133(3):1339–1345. [PubMed] [Google Scholar]
  27. Kern J. A., Lamb R. J., Reed J. C., Daniele R. P., Nowell P. C. Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms. J Clin Invest. 1988 Jan;81(1):237–244. doi: 10.1172/JCI113301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Knudsen P. J., Dinarello C. A., Strom T. B. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol. 1987 Dec 15;139(12):4129–4134. [PubMed] [Google Scholar]
  29. Knudsen P. J., Dinarello C. A., Strom T. B. Prostaglandins posttranscriptionally inhibit monocyte expression of interleukin 1 activity by increasing intracellular cyclic adenosine monophosphate. J Immunol. 1986 Nov 15;137(10):3189–3194. [PubMed] [Google Scholar]
  30. Kunkel S. L., Chensue S. W., Phan S. H. Prostaglandins as endogenous mediators of interleukin 1 production. J Immunol. 1986 Jan;136(1):186–192. [PubMed] [Google Scholar]
  31. Lee S. W., Tsou A. P., Chan H., Thomas J., Petrie K., Eugui E. M., Allison A. C. Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1204–1208. doi: 10.1073/pnas.85.4.1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lehrach H., Diamond D., Wozney J. M., Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. doi: 10.1021/bi00640a033. [DOI] [PubMed] [Google Scholar]
  33. Lew W., Oppenheim J. J., Matsushima K. Analysis of the suppression of IL-1 alpha and IL-1 beta production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone. J Immunol. 1988 Mar 15;140(6):1895–1902. [PubMed] [Google Scholar]
  34. Murray H. W. Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med. 1988 Apr;108(4):595–608. doi: 10.7326/0003-4819-108-4-595. [DOI] [PubMed] [Google Scholar]
  35. Myers R. F., Siegel M. I. Differential effects of anti-inflammatory drugs on lipoxygenase and cyclo-oxygenase activities of neutrophils from a reverse passive Arthus reaction. Biochem Biophys Res Commun. 1983 Apr 29;112(2):586–594. doi: 10.1016/0006-291x(83)91504-8. [DOI] [PubMed] [Google Scholar]
  36. Nathan C. F. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. doi: 10.1172/JCI112815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ozaki Y., Ohashi T., Minami A., Nakamura S. Enhanced resistance of mice to bacterial infection induced by recombinant human interleukin-1a. Infect Immun. 1987 Jun;55(6):1436–1440. doi: 10.1128/iai.55.6.1436-1440.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Paajanen H., Männistö J., Uotila P. Aspirin inhibits arachidonic acid metabolism via lipoxygenase and cyclo-oxygenase in hamster isolated lungs. Prostaglandins. 1982 May;23(5):731–741. doi: 10.1016/s0090-6980(82)80011-7. [DOI] [PubMed] [Google Scholar]
  39. Pearson R. D., Wheeler D. A., Harrison L. H., Kay H. D. The immunobiology of leishmaniasis. Rev Infect Dis. 1983 Sep-Oct;5(5):907–927. doi: 10.1093/clinids/5.5.907. [DOI] [PubMed] [Google Scholar]
  40. Pearson R. D., de Alencar J. E., Romito R., Naidu T. G., Young A. C., Davis J. S., 4th Circulating immune complexes and rheumatoid factors in visceral leishmaniasis. J Infect Dis. 1983 Jun;147(6):1102–1102. doi: 10.1093/infdis/147.6.1102. [DOI] [PubMed] [Google Scholar]
  41. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  42. Reiner N. E., Finke J. H. Interleukin 2 deficiency in murine Leishmaniasis donovani and its relationship to depressed spleen cell responses to phytohemagglutinin. J Immunol. 1983 Sep;131(3):1487–1491. [PubMed] [Google Scholar]
  43. Reiner N. E. Host-parasite relationship in murine leishmaniasis: pathophysiological and immunological changes. Infect Immun. 1982 Dec;38(3):1223–1230. doi: 10.1128/iai.38.3.1223-1230.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reiner N. E., Malemud C. J. Arachidonic acid metabolism by murine peritoneal macrophages infected with Leishmania donovani: in vitro evidence for parasite-induced alterations in cyclooxygenase and lipoxygenase pathways. J Immunol. 1985 Jan;134(1):556–563. [PubMed] [Google Scholar]
  45. Reiner N. E., Ng W., Ma T., McMaster W. R. Kinetics of gamma interferon binding and induction of major histocompatibility complex class II mRNA in Leishmania-infected macrophages. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4330–4334. doi: 10.1073/pnas.85.12.4330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. 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]
  47. Rola-Pleszczynski M., Lemaire I. Leukotrienes augment interleukin 1 production by human monocytes. J Immunol. 1985 Dec;135(6):3958–3961. [PubMed] [Google Scholar]
  48. Russell S. W., Pace J. L. Gamma interferon interferes with the negative regulation of macrophage activation by prostaglandin E2. Mol Immunol. 1984 Mar;21(3):249–254. doi: 10.1016/0161-5890(84)90080-4. [DOI] [PubMed] [Google Scholar]
  49. Titus R. G., Sherry B., Cerami A. Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis. J Exp Med. 1989 Dec 1;170(6):2097–2104. doi: 10.1084/jem.170.6.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Unanue E. R., Allen P. M. The basis for the immunoregulatory role of macrophages and other accessory cells. Science. 1987 May 1;236(4801):551–557. doi: 10.1126/science.2437650. [DOI] [PubMed] [Google Scholar]

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