Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Jun;65(6):2100–2106. doi: 10.1128/iai.65.6.2100-2106.1997

Temporal effect of tumor necrosis factor alpha on murine macrophages infected with Mycobacterium avium.

I S Eriks 1, C L Emerson 1
PMCID: PMC175290  PMID: 9169738

Abstract

Members of the Mycobacterium avium complex are a family of bacteria that persist within macrophages in the face of an immune response. Elimination of these organisms is likely due to cytokine-induced macrophage activation. Because macrophage activation by tumor necrosis factor alpha (TNF-alpha) appears critical for killing of intracellular M. avium, early downregulation of TNF-alpha levels in infected macrophages has been suggested as a survival mechanism for virulent strains of M. avium. We examined the relationship between TNF-alpha and growth of M. avium strains of differing virulence, as measured by their ability to grow in murine bone marrow-derived macrophages. When exogenous TNF-alpha was added immediately following macrophage infection, significant growth inhibition of virulent M. avium strains was observed. If TNF-alpha addition was delayed by 24 h or more, growth inhibition was abrogated. To determine if early downregulation of TNF-alpha levels could explain the differential growth of virulent and avirulent strains, levels of TNF-alpha and prostaglandin E2 (PGE2), which has been shown to suppress TNF-alpha production in uninfected macrophages, were quantified over time. Upregulation of both TNF-alpha and PGE2, as measured by enzyme-linked immunosorbent assay, was evident by 6 h postinfection, indicating that the ability of M. avium to replicate in macrophages was not directly correlated with early downregulation of TNF-alpha production. However, TNF-alpha bioactivity, as measured by cytotoxicity, was significantly decreased in virulent M. avium strains at all time periods examined. Treatment of infected macrophages with gamma interferon immediately after infection resulted in significantly increased levels of nitric oxide but did not affect the growth of virulent M. avium strains. These results suggest that while significant levels of TNF-alpha are present in supernatants from all M. avium strains, levels of biologically active TNF-alpha are significantly reduced in supernatants from virulent M. avium strains. Preliminary results suggest that upregulation of the soluble p75 TNF receptor may be one mechanism by which TNF-alpha bioactivity reduction occurs.

Full Text

The Full Text of this article is available as a PDF (272.5 KB).

Selected References

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

  1. Alleva D. G., Burger C. J., Elgert K. D. Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2. J Immunol. 1994 Aug 15;153(4):1674–1686. [PubMed] [Google Scholar]
  2. Appelberg R., Castro A. G., Pedrosa J., Silva R. A., Orme I. M., Minóprio P. Role of gamma interferon and tumor necrosis factor alpha during T-cell-independent and -dependent phases of Mycobacterium avium infection. Infect Immun. 1994 Sep;62(9):3962–3971. doi: 10.1128/iai.62.9.3962-3971.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Appelberg R., Orme I. M. Effector mechanisms involved in cytokine-mediated bacteriostasis of Mycobacterium avium infections in murine macrophages. Immunology. 1993 Nov;80(3):352–359. [PMC free article] [PubMed] [Google Scholar]
  4. Arai T., Hiromatsu K., Nishimura H., Kimura Y., Kobayashi N., Ishida H., Nimura Y., Yoshikai Y. Endogenous interleukin 10 prevents apoptosis in macrophages during Salmonella infection. Biochem Biophys Res Commun. 1995 Aug 15;213(2):600–607. doi: 10.1006/bbrc.1995.2174. [DOI] [PubMed] [Google Scholar]
  5. Bermudez L. E., Stevens P., Kolonoski P., Wu M., Young L. S. Treatment of experimental disseminated Mycobacterium avium complex infection in mice with recombinant IL-2 and tumor necrosis factor. J Immunol. 1989 Nov 1;143(9):2996–3000. [PubMed] [Google Scholar]
  6. Bermudez L. E., Wu M., Petrofsky M., Young L. S. Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in macrophages. Infect Immun. 1992 Oct;60(10):4245–4252. doi: 10.1128/iai.60.10.4245-4252.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Branch D. R., Shah A., Guilbert L. J. A specific and reliable bioassay for the detection of femtomolar levels of human and murine tumor necrosis factors. J Immunol Methods. 1991 Oct 25;143(2):251–261. doi: 10.1016/0022-1759(91)90050-p. [DOI] [PubMed] [Google Scholar]
  9. Braun R. K., Buergelt C. D., Littell R. C., Linda S. B., Simpson J. R. Use of an enzyme-linked immunosorbent assay to estimate prevalence of paratuberculosis in cattle of Florida. J Am Vet Med Assoc. 1990 Apr 15;196(8):1251–1254. [PubMed] [Google Scholar]
  10. Carvalho de Sousa J. P., Bachelet M., Rastogi N. Effect of indomethacin on the modulation of Mycobacterium avium growth in human macrophages by interferon gamma, retinoic acid and 1,25(OH)2-vitamin D3. FEMS Microbiol Immunol. 1992 Jul;4(5):281–286. doi: 10.1111/j.1574-6968.1992.tb05007.x. [DOI] [PubMed] [Google Scholar]
  11. Champsi J., Young L. S., Bermudez L. E. Production of TNF-alpha, IL-6 and TGF-beta, and expression of receptors for TNF-alpha and IL-6, during murine Mycobacterium avium infection. Immunology. 1995 Apr;84(4):549–554. [PMC free article] [PubMed] [Google Scholar]
  12. Chiodini R. J., Davis W. C. The cellular immunology of bovine paratuberculosis: immunity may be regulated by CD4+ helper and CD8+ immunoregulatory T lymphocytes which down-regulate gamma/delta+ T-cell cytotoxicity. Microb Pathog. 1993 May;14(5):355–367. doi: 10.1006/mpat.1993.1035. [DOI] [PubMed] [Google Scholar]
  13. Chiodini R. J., Davis W. C. The cellular immunology of bovine paratuberculosis: the predominant response is mediated by cytotoxic gamma/delta T lymphocytes which prevent CD4+ activity. Microb Pathog. 1992 Dec;13(6):447–463. doi: 10.1016/0882-4010(92)90012-d. [DOI] [PubMed] [Google Scholar]
  14. Denis M., Gregg E. O. Modulation of Mycobacterium avium growth in murine macrophages: reversal of unresponsiveness to interferon-gamma by indomethacin or interleukin-4. J Leukoc Biol. 1991 Jan;49(1):65–72. doi: 10.1002/jlb.49.1.65. [DOI] [PubMed] [Google Scholar]
  15. Denis M. Modulation of Mycobacterium avium growth in vivo by cytokines: involvement of tumour necrosis factor in resistance to atypical mycobacteria. Clin Exp Immunol. 1991 Mar;83(3):466–471. doi: 10.1111/j.1365-2249.1991.tb05662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Ding A. H., Nathan C. F., Stuehr D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed] [Google Scholar]
  18. Dumarey C. H., Labrousse V., Rastogi N., Vargaftig B. B., Bachelet M. Selective Mycobacterium avium-induced production of nitric oxide by human monocyte-derived macrophages. J Leukoc Biol. 1994 Jul;56(1):36–40. doi: 10.1002/jlb.56.1.36. [DOI] [PubMed] [Google Scholar]
  19. Flesch I. E., Kaufmann S. H. Mechanisms involved in mycobacterial growth inhibition by gamma interferon-activated bone marrow macrophages: role of reactive nitrogen intermediates. Infect Immun. 1991 Sep;59(9):3213–3218. doi: 10.1128/iai.59.9.3213-3218.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Friedland J. S., Shattock R. J., Johnson J. D., Remick D. G., Holliman R. E., Griffin G. E. Differential cytokine gene expression and secretion after phagocytosis by a human monocytic cell line of Toxoplasma gondii compared with Mycobacterium tuberculosis. Clin Exp Immunol. 1993 Feb;91(2):282–286. doi: 10.1111/j.1365-2249.1993.tb05896.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Furney S. K., Skinner P. S., Roberts A. D., Appelberg R., Orme I. M. Capacity of Mycobacterium avium isolates to grow well or poorly in murine macrophages resides in their ability to induce secretion of tumor necrosis factor. Infect Immun. 1992 Oct;60(10):4410–4413. doi: 10.1128/iai.60.10.4410-4413.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hibbs J. B., Jr, Taintor R. R., Vavrin Z., Rachlin E. M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. doi: 10.1016/s0006-291x(88)80015-9. [DOI] [PubMed] [Google Scholar]
  23. Holtmann H., Hahn T., Wallach D. Interrelated effects of tumor necrosis factor and interleukin 1 on cell viability. Immunobiology. 1988 Apr;177(1):7–22. doi: 10.1016/S0171-2985(88)80087-1. [DOI] [PubMed] [Google Scholar]
  24. Linderholm M., Ahlm C., Settergren B., Waage A., Tärnvik A. Elevated plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, and IL-10 in patients with hemorrhagic fever with renal syndrome. J Infect Dis. 1996 Jan;173(1):38–43. doi: 10.1093/infdis/173.1.38. [DOI] [PubMed] [Google Scholar]
  25. Merkal R. S., Whipple D. L., Sacks J. M., Snyder G. R. Prevalence of Mycobacterium paratuberculosis in ileocecal lymph nodes of cattle culled in the United States. J Am Vet Med Assoc. 1987 Mar 15;190(6):676–680. [PubMed] [Google Scholar]
  26. Orme I. M., Furney S. K., Skinner P. S., Roberts A. D., Brennan P. J., Russell D. G., Shiratsuchi H., Ellner J. J., Weiser W. Y. Inhibition of growth of Mycobacterium avium in murine and human mononuclear phagocytes by migration inhibitory factor. Infect Immun. 1993 Jan;61(1):338–342. doi: 10.1128/iai.61.1.338-342.1993. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  27. Pontzer C. H., Russell S. W. Culture of macrophages from bovine bone marrow. Vet Immunol Immunopathol. 1989 Jul;21(3-4):351–362. doi: 10.1016/0165-2427(89)90042-1. [DOI] [PubMed] [Google Scholar]
  28. Tsang A. Y., Denner J. C., Brennan P. J., McClatchy J. K. Clinical and epidemiological importance of typing of Mycobacterium avium complex isolates. J Clin Microbiol. 1992 Feb;30(2):479–484. doi: 10.1128/jcm.30.2.479-484.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Warren M. K., Vogel S. N. Bone marrow-derived macrophages: development and regulation of differentiation markers by colony-stimulating factor and interferons. J Immunol. 1985 Feb;134(2):982–989. [PubMed] [Google Scholar]
  30. Wu J., Cunha F. Q., Liew F. Y., Weiser W. Y. IL-10 inhibits the synthesis of migration inhibitory factor and migration inhibitory factor-mediated macrophage activation. J Immunol. 1993 Oct 15;151(8):4325–4332. [PubMed] [Google Scholar]
  31. Young L. S. Mycobacterium avium complex infection. J Infect Dis. 1988 May;157(5):863–867. doi: 10.1093/infdis/157.5.863. [DOI] [PubMed] [Google Scholar]

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

RESOURCES