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. 1997 Dec;65(12):5149–5156. doi: 10.1128/iai.65.12.5149-5156.1997

Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis.

M J Fenton 1, M W Vermeulen 1, S Kim 1, M Burdick 1, R M Strieter 1, H Kornfeld 1
PMCID: PMC175742  PMID: 9393809

Abstract

Gamma interferon (IFN-gamma) is a cytokine which plays a critical role in resistance to Mycobacterium tuberculosis infection. While T lymphocytes and natural killer cells are a major source of IFN-gamma, previous demonstrations that it can be produced by murine macrophages prompted us to examine the capacity of human alveolar macrophages to express IFN-gamma. Here we report that in vitro infection of alveolar macrophages with M. tuberculosis induces both the release of IFN-gamma protein and a transient increase in IFN-gamma mRNA levels. The IFN-producing cells were shown to be macrophages by reverse transcription-in situ PCR. We also observed that M. tuberculosis stimulation resulted in IFN-gamma-dependent expression of the chemokines IFN-gamma-inducible protein 10 and monokine induced by IFN-gamma, suggesting that macrophage-derived IFN-gamma can function in an autocrine and/or paracrine manner. The existence of a positive regulatory loop was suggested by the observation that exogenous IFN-gamma protein could induce IFN-gamma mRNA expression in uninfected alveolar macrophages. Interleukin-12 was also found to be a potent inducer of IFN-gamma production, and M. tuberculosis-induced IFN-gamma production appears to be mediated, at least in part, by IL-12. In contrast, M. tuberculosis-induced IFN-gamma production by alveolar macrophages could be blocked by exogenous interleukin-10. These studies are the first to demonstrate an autoregulatory role for IFN-gamma produced by alveolar macrophages infected in vitro with M. tuberculosis.

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Selected References

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  1. Arenberg D. A., Kunkel S. L., Polverini P. J., Morris S. B., Burdick M. D., Glass M. C., Taub D. T., Iannettoni M. D., Whyte R. I., Strieter R. M. Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J Exp Med. 1996 Sep 1;184(3):981–992. doi: 10.1084/jem.184.3.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barnes P. F., Fong S. J., Brennan P. J., Twomey P. E., Mazumder A., Modlin R. L. Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis. J Immunol. 1990 Jul 1;145(1):149–154. [PubMed] [Google Scholar]
  3. Bernaudin J. F., Yamauchi K., Wewers M. D., Tocci M. J., Ferrans V. J., Crystal R. G. Demonstration by in situ hybridization of dissimilar IL-1 beta gene expression in human alveolar macrophages and blood monocytes in response to lipopolysaccharide. J Immunol. 1988 Jun 1;140(11):3822–3829. [PubMed] [Google Scholar]
  4. Blanchard D. K., Michelini-Norris M. B., Pearson C. A., McMillen S., Djeu J. Y. Production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by monocytes and large granular lymphocytes stimulated with Mycobacterium avium-M. intracellulare: activation of bactericidal activity by GM-CSF. Infect Immun. 1991 Jul;59(7):2396–2402. doi: 10.1128/iai.59.7.2396-2402.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carvalho de Sousa J. P., Rastogi N. Comparative ability of human monocytes and macrophages to control the intracellular growth of Mycobacterium avium and Mycobacterium tuberculosis: effect of interferon-gamma and indomethacin. FEMS Microbiol Immunol. 1992 Aug;4(6):329–334. doi: 10.1111/j.1574-6968.1992.tb05013.x. [DOI] [PubMed] [Google Scholar]
  6. Chan J., Xing Y., Magliozzo R. S., Bloom B. R. Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. J Exp Med. 1992 Apr 1;175(4):1111–1122. doi: 10.1084/jem.175.4.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chomarat P., Rissoan M. C., Banchereau J., Miossec P. Interferon gamma inhibits interleukin 10 production by monocytes. J Exp Med. 1993 Feb 1;177(2):523–527. doi: 10.1084/jem.177.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G., Orme I. M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. doi: 10.1084/jem.178.6.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  10. Denis M., Gregg E. O. Recombinant tumour necrosis factor-alpha decreases whereas recombinant interleukin-6 increases growth of a virulent strain of Mycobacterium avium in human macrophages. Immunology. 1990 Sep;71(1):139–141. [PMC free article] [PubMed] [Google Scholar]
  11. Di Marzio P., Puddu P., Conti L., Belardelli F., Gessani S. Interferon gamma upregulates its own gene expression in mouse peritoneal macrophages. J Exp Med. 1994 May 1;179(5):1731–1736. doi: 10.1084/jem.179.5.1731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Donnelly R. P., Freeman S. L., Hayes M. P. Inhibition of IL-10 expression by IFN-gamma up-regulates transcription of TNF-alpha in human monocytes. J Immunol. 1995 Aug 1;155(3):1420–1427. [PubMed] [Google Scholar]
  13. Douvas G. S., Looker D. L., Vatter A. E., Crowle A. J. Gamma interferon activates human macrophages to become tumoricidal and leishmanicidal but enhances replication of macrophage-associated mycobacteria. Infect Immun. 1985 Oct;50(1):1–8. doi: 10.1128/iai.50.1.1-8.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Farber J. M. HuMig: a new human member of the chemokine family of cytokines. Biochem Biophys Res Commun. 1993 Apr 15;192(1):223–230. doi: 10.1006/bbrc.1993.1403. [DOI] [PubMed] [Google Scholar]
  15. Fenton M. J., Vermeulen M. W. Immunopathology of tuberculosis: roles of macrophages and monocytes. Infect Immun. 1996 Mar;64(3):683–690. doi: 10.1128/iai.64.3.683-690.1996. [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. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fulton S. A., Johnsen J. M., Wolf S. F., Sieburth D. S., Boom W. H. Interleukin-12 production by human monocytes infected with Mycobacterium tuberculosis: role of phagocytosis. Infect Immun. 1996 Jul;64(7):2523–2531. doi: 10.1128/iai.64.7.2523-2531.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fultz M. J., Barber S. A., Dieffenbach C. W., Vogel S. N. Induction of IFN-gamma in macrophages by lipopolysaccharide. Int Immunol. 1993 Nov;5(11):1383–1392. doi: 10.1093/intimm/5.11.1383. [DOI] [PubMed] [Google Scholar]
  20. Gong J. H., Zhang M., Modlin R. L., Linsley P. S., Iyer D., Lin Y., Barnes P. F. Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect Immun. 1996 Mar;64(3):913–918. doi: 10.1128/iai.64.3.913-918.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Green L. C., Wagner D. A., Glogowski J., Skipper P. L., Wishnok J. S., Tannenbaum S. R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  22. Jouanguy E., Altare F., Lamhamedi S., Revy P., Emile J. F., Newport M., Levin M., Blanche S., Seboun E., Fischer A. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection. N Engl J Med. 1996 Dec 26;335(26):1956–1961. doi: 10.1056/NEJM199612263352604. [DOI] [PubMed] [Google Scholar]
  23. Keane J., Balcewicz-Sablinska M. K., Remold H. G., Chupp G. L., Meek B. B., Fenton M. J., Kornfeld H. Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect Immun. 1997 Jan;65(1):298–304. doi: 10.1128/iai.65.1.298-304.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kotloff R. M., Little J., Elias J. A. Human alveolar macrophage and blood monocyte interleukin-6 production. Am J Respir Cell Mol Biol. 1990 Nov;3(5):497–505. doi: 10.1165/ajrcmb/3.5.497. [DOI] [PubMed] [Google Scholar]
  25. Luster A. D., Ravetch J. V. Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med. 1987 Oct 1;166(4):1084–1097. doi: 10.1084/jem.166.4.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Luster A. D., Unkeless J. C., Ravetch J. V. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985 Jun 20;315(6021):672–676. doi: 10.1038/315672a0. [DOI] [PubMed] [Google Scholar]
  27. Newport M. J., Huxley C. M., Huston S., Hawrylowicz C. M., Oostra B. A., Williamson R., Levin M. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996 Dec 26;335(26):1941–1949. doi: 10.1056/NEJM199612263352602. [DOI] [PubMed] [Google Scholar]
  28. Ohmori Y., Hamilton T. A. The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-gamma and TNF-alpha. J Immunol. 1995 May 15;154(10):5235–5244. [PubMed] [Google Scholar]
  29. Orme I. M., Roberts A. D., Griffin J. P., Abrams J. S. Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection. J Immunol. 1993 Jul 1;151(1):518–525. [PubMed] [Google Scholar]
  30. Pue C. A., Mortensen R. F., Marsh C. B., Pope H. A., Wewers M. D. Acute phase levels of C-reactive protein enhance IL-1 beta and IL-1ra production by human blood monocytes but inhibit IL-1 beta and IL-1ra production by alveolar macrophages. J Immunol. 1996 Feb 15;156(4):1594–1600. [PubMed] [Google Scholar]
  31. Rich E. A., Panuska J. R., Wallis R. S., Wolf C. B., Leonard M. L., Ellner J. J. Dyscoordinate expression of tumor necrosis factor-alpha by human blood monocytes and alveolar macrophages. Am Rev Respir Dis. 1989 Apr;139(4):1010–1016. doi: 10.1164/ajrccm/139.4.1010. [DOI] [PubMed] [Google Scholar]
  32. Robinson D. S., Ying S., Taylor I. K., Wangoo A., Mitchell D. M., Kay A. B., Hamid Q., Shaw R. J. Evidence for a Th1-like bronchoalveolar T-cell subset and predominance of interferon-gamma gene activation in pulmonary tuberculosis. Am J Respir Crit Care Med. 1994 Apr;149(4 Pt 1):989–993. doi: 10.1164/ajrccm.149.4.8143065. [DOI] [PubMed] [Google Scholar]
  33. Rook G. A., Steele J., Ainsworth M., Champion B. R. Activation of macrophages to inhibit proliferation of Mycobacterium tuberculosis: comparison of the effects of recombinant gamma-interferon on human monocytes and murine peritoneal macrophages. Immunology. 1986 Nov;59(3):333–338. [PMC free article] [PubMed] [Google Scholar]
  34. Shimokata K., Saka H., Murate T., Hasegawa Y., Hasegawa T. Cytokine content in pleural effusion. Comparison between tuberculous and carcinomatous pleurisy. Chest. 1991 May;99(5):1103–1107. doi: 10.1378/chest.99.5.1103. [DOI] [PubMed] [Google Scholar]
  35. Wallis R. S., Ellner J. J. Cytokines and tuberculosis. J Leukoc Biol. 1994 May;55(5):676–681. doi: 10.1002/jlb.55.5.676. [DOI] [PubMed] [Google Scholar]
  36. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  37. Young H. A., Hardy K. J. Role of interferon-gamma in immune cell regulation. J Leukoc Biol. 1995 Oct;58(4):373–381. [PubMed] [Google Scholar]
  38. Zhang M., Gately M. K., Wang E., Gong J., Wolf S. F., Lu S., Modlin R. L., Barnes P. F. Interleukin 12 at the site of disease in tuberculosis. J Clin Invest. 1994 Apr;93(4):1733–1739. doi: 10.1172/JCI117157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zhang M., Gong J., Iyer D. V., Jones B. E., Modlin R. L., Barnes P. F. T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest. 1994 Dec;94(6):2435–2442. doi: 10.1172/JCI117611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zhang M., Lin Y., Iyer D. V., Gong J., Abrams J. S., Barnes P. F. T-cell cytokine responses in human infection with Mycobacterium tuberculosis. Infect Immun. 1995 Aug;63(8):3231–3234. doi: 10.1128/iai.63.8.3231-3234.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. de Waal Malefyt R., Yssel H., de Vries J. E. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed] [Google Scholar]

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