Role of tumor necrosis factor-alpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice

Lab Invest. 1999 Apr;79(4):379-86.


To study the role of TNF-alpha in mycobacterial infection, we generated TNF-alpha-knockout (KO) mice, in which the third and fourth exons of the TNF-alpha gene were disrupted. The C57BL/6 KO mice were injected with virulent Mycobacterium tuberculosis strain Kurono or avirulent bacillus Calmette-Guérin (BCG) Pasteur (10(6) colony-forming units), through the tail veins. The major organs were removed at weekly intervals, and morphologic observation, assays of IL-1, IL-12, IFN-gamma, and inducible nitric oxide synthase mRNA expression, and colony counts in the lungs and spleen were performed. Peritoneal macrophages from BCG- and H37Rv strain-treated mice produced significant levels of nitric oxide after stimulation in vitro. Formation of abscesses was seen only in the Kurono-treated groups, and these abscesses contained large numbers of mycobacteria. The administration of recombinant TNF-alpha significantly ameliorated the mycobacterial lesions. IFN-gamma mRNA was expressed significantly in virulent H37Rv-treated groups with time, and the number of mycobacterial colonies per unit weight increased remarkably with time. Nitric oxide production was not observed in H37Rv-treated groups but was seen in BCG-treated groups. We concluded that TNF-alpha played an important role in protective immunity against virulent mycobacteria. Because avirulent mycobacteria did not induce granulomas in TNF-alpha-KO mice, TNF-alpha played an indirect role in granuloma formation.

MeSH terms

  • Animals
  • Exons
  • Granuloma / genetics*
  • Granuloma / microbiology*
  • Granuloma / pathology
  • Interferon-gamma / genetics
  • Interleukin-1 / genetics
  • Interleukin-12 / genetics
  • Lung / immunology
  • Lung / microbiology
  • Lung / pathology
  • Lung Abscess / immunology
  • Lung Abscess / microbiology
  • Lung Abscess / pathology
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium bovis
  • Mycobacterium tuberculosis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Spleen / immunology
  • Spleen / microbiology
  • Spleen / pathology
  • Transcription, Genetic
  • Tuberculosis, Pulmonary / genetics*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / pathology
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*


  • Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse