Role of tumor necrosis factor-alpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice.
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.
Kaneko
H
H
Department of Molecular Pathology, The Research Institute of Tuberculosis, Kiyose, Tokyo, Japan.
Yamada
H
H
Mizuno
S
S
Udagawa
T
T
Kazumi
Y
Y
Sekikawa
K
K
Sugawara
I
I
D000818:Animals; D005091:Exons; D006099:Granuloma / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008169:Lung Abscess / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis; D009169:Mycobacterium tuberculosis; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014158:Transcription, Genetic; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse