Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages

John Chan, Yun Xing, Richard S. Magliozzo, Barry R. Bloom

Research output: Contribution to journalArticle

800 Citations (Scopus)

Abstract

Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon γ, and lipopolysaccharide or tumor necrosis factor α, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line D9, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymatically generated H2O2, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the L-arginine-dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the micobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the L-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)1111-1122
Number of pages12
JournalJournal of Experimental Medicine
Volume175
Issue number4
StatePublished - Apr 1 1992
Externally publishedYes

Fingerprint

Mycobacterium tuberculosis
Nitrogen
Macrophages
Oxygen
Superoxide Dismutase
Arginine
Reactive Oxygen Species
Cell Line
Poisons
Peritoneal Macrophages
Mannitol
Growth
Catalase
Interferons
Lipopolysaccharides
Tuberculosis
Tumor Necrosis Factor-alpha
Morbidity
Mortality

ASJC Scopus subject areas

  • Immunology

Cite this

Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. / Chan, John; Xing, Yun; Magliozzo, Richard S.; Bloom, Barry R.

In: Journal of Experimental Medicine, Vol. 175, No. 4, 01.04.1992, p. 1111-1122.

Research output: Contribution to journalArticle

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