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Infect Immun. 1996 Feb; 64(2): 452–459.
PMCID: PMC173785

H2O2 induces monocyte apoptosis and reduces viability of Mycobacterium avium-M. intracellulare within cultured human monocytes.


Mycobacterium avium-M. intracellulare, an intracellular parasite of mononuclear phagocytes, rarely causes disease in immunocompetent individuals. In contrast, in human immunodeficiency virus type 1-infected patients, M. avium-M. intracellulare can infect almost every tissue and organ. This suggests that immunocompetent individuals have a protective mechanism to control or prevent the infection. How mycobacterial may be killed by the host immune response is unclear. We have recently reported that induction of apoptosis of Mycobacterium bovis BCG-infected macrophages with ATP4- was associated with killing of the intracellular mycobacteria. In the present study, a long-term culture of M. avium-M. intracellulare-infected monocytes was used to further evaluate the interaction between M. avium-M. intracellulare and primary human monocytes. In our system, M. avium-M. intracellulare parasitized the human monocytes and appeared to replicate slowly over 14 days within the host cells. To examine the role of apoptotic mechanisms in survival or death of intracellular mycobacteria, M. avium-M. intracellulare-infected human monocytes were treated with a monoclonal antibody to Fas receptor (APO-1/CD95) or with various concentrations of H2O2. Although both of these exogenous agents induced monocyte apoptosis, optimal killing (65% reduction in CFU) of intracellular M. avium-M. intracellulare was observed only when M. avium-M. intracellulare-infected cells were treated with 10 mM H2O2. Fas-induced apoptosis did not affect M. avium-M. intracellulare viability. Our results suggest that not all stimuli of monocyte apoptosis induce killing of intracellular M. avium-M. intracellulare. Since release of H2O2 following phagocytosis of mycobacteria has been documented, H2O2-induced apoptotic death of M. avium-M. intracellulare-infected monocytes and its association with killing of the intracellular bacilli may be a physiological mechanism of host defense against M. avium-M. intracellulare.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bermudez LE, Kaplan G. Recombinant cytokines for controlling mycobacterial infections. Trends Microbiol. 1995 Jan;3(1):22–27. [PubMed]
  • Bermudez LE, Young LS. 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]
  • Bermudez LE, Young LS. Oxidative and non-oxidative intracellular killing of Mycobacterium avium complex. Microb Pathog. 1989 Oct;7(4):289–298. [PubMed]
  • Blanchard DK, Michelini-Norris MB, Djeu JY. Interferon decreases the growth inhibition of Mycobacterium avium-intracellulare complex by fresh human monocytes but not by culture-derived macrophages. J Infect Dis. 1991 Jul;164(1):152–157. [PubMed]
  • Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. [PubMed]
  • Cameron ML, Granger DL, Weinberg JB, Kozumbo WJ, Koren HS. Human alveolar and peritoneal macrophages mediate fungistasis independently of L-arginine oxidation to nitrite or nitrate. Am Rev Respir Dis. 1990 Dec;142(6 Pt 1):1313–1319. [PubMed]
  • Chapman JS. The atypical mycobacteria. Am Rev Respir Dis. 1982 Mar;125(3 Pt 2):1l9–124. [PubMed]
  • Chester AC, Winn WC., Jr Unusual and newly recognized patterns of nontuberculous mycobacterial infection with emphasis on the immunocompromised host. Pathol Annu. 1986;21(Pt 1):251–270. [PubMed]
  • Cohen JJ. Apoptosis. Immunol Today. 1993 Mar;14(3):126–130. [PubMed]
  • Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. [PMC free article] [PubMed]
  • Crowle AJ, Tsang AY, Vatter AE, May MH. Comparison of 15 laboratory and patient-derived strains of Mycobacterium avium for ability to infect and multiply in cultured human macrophages. J Clin Microbiol. 1986 Nov;24(5):812–821. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Deo MG. Immunological approach for control of Mycobacterium avium-intracellulare infections in AIDS-an hypothesis. Int J Lepr Other Mycobact Dis. 1988 Sep;56(3):455–463. [PubMed]
  • Doherty PC. Cell-mediated cytotoxicity. Cell. 1993 Nov 19;75(4):607–612. [PubMed]
  • Gangadharam PR, Edwards CK., 3rd Release of superoxide anion from resident and activated mouse peritoneal macrophages infected with Mycobacterium intracellulare. Am Rev Respir Dis. 1984 Nov;130(5):834–838. [PubMed]
  • Gordon AH, Hart PD. Stimulation or inhibition of the respiratory burst in cultured macrophages in a mycobacterium model: initial stimulation is followed by inhibition after phagocytosis. Infect Immun. 1994 Oct;62(10):4650–4651. [PMC free article] [PubMed]
  • Green PA, von Reyn CF, Smith RP., Jr Mycobacterium avium complex parotid lymphadenitis: successful therapy with clarithromycin and ethambutol. Pediatr Infect Dis J. 1993 Jul;12(7):615–617. [PubMed]
  • Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA. Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha. J Immunol. 1990 Dec 15;145(12):4290–4297. [PubMed]
  • Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1–85. [PubMed]
  • Hirose K, Longo DL, Oppenheim JJ, Matsushima K. Overexpression of mitochondrial manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin-1, tumor necrosis factor, selected anticancer drugs, and ionizing radiation. FASEB J. 1993 Feb 1;7(2):361–368. [PubMed]
  • Hug H, Enari M, Nagata S. No requirement of reactive oxygen intermediates in Fas-mediated apoptosis. FEBS Lett. 1994 Sep 12;351(3):311–313. [PubMed]
  • Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. [PubMed]
  • Iwai K, Miyawaki T, Takizawa T, Konno A, Ohta K, Yachie A, Seki H, Taniguchi N. Differential expression of bcl-2 and susceptibility to anti-Fas-mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils. Blood. 1994 Aug 15;84(4):1201–1208. [PubMed]
  • James SL, Cook KW, Lazdins JK. Activation of human monocyte-derived macrophages to kill schistosomula of Schistosoma mansoni in vitro. J Immunol. 1990 Oct 15;145(8):2686–2690. [PubMed]
  • Johnson JL, Shiratsuchi H, Toba H, Ellner JJ. Preservation of monocyte effector functions against Mycobacterium avium-M. intracellulare in patients with AIDS. Infect Immun. 1991 Oct;59(10):3639–3645. [PMC free article] [PubMed]
  • Leithäuser F, Dhein J, Mechtersheimer G, Koretz K, Brüderlein S, Henne C, Schmidt A, Debatin KM, Krammer PH, Möller P. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab Invest. 1993 Oct;69(4):415–429. [PubMed]
  • Lennon SV, Martin SJ, Cotter TG. Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli. Cell Prolif. 1991 Mar;24(2):203–214. [PubMed]
  • Lepay DA, Steinman RM, Nathan CF, Murray HW, Cohn ZA. Liver macrophages in murine listeriosis. Cell-mediated immunity is correlated with an influx of macrophages capable of generating reactive oxygen intermediates. J Exp Med. 1985 Jun 1;161(6):1503–1512. [PMC free article] [PubMed]
  • Molloy A, Laochumroonvorapong P, Kaplan G. Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular bacillus Calmette-Guérin. J Exp Med. 1994 Oct 1;180(4):1499–1509. [PMC free article] [PubMed]
  • Molloy A, Meyn PA, Smith KD, Kaplan G. Recognition and destruction of Bacillus Calmette-Guerin-infected human monocytes. J Exp Med. 1993 Jun 1;177(6):1691–1698. [PMC free article] [PubMed]
  • Murray HW, Teitelbaum RF. L-arginine-dependent reactive nitrogen intermediates and the antimicrobial effect of activated human mononuclear phagocytes. J Infect Dis. 1992 Mar;165(3):513–517. [PubMed]
  • Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993 Aug 26;364(6440):806–809. [PubMed]
  • Padgett EL, Pruett SB. Evaluation of nitrite production by human monocyte-derived macrophages. Biochem Biophys Res Commun. 1992 Jul 31;186(2):775–781. [PubMed]
  • Raszka WV, Jr, Trinh TT, Zawadsky PM. Multifocal M. intracellulare osteomyelitis in an immunocompetent child. Clin Pediatr (Phila) 1994 Oct;33(10):611–616. [PubMed]
  • Saito H, Tomioka H. The role of macrophages in host defence mechanisms against Mycobacterium avium complex infection induced in mice. Res Microbiol. 1990 Feb;141(2):206–212. [PubMed]
  • Sasada M, Johnston RB., Jr Macrophage microbicidal activity. Correlation between phagocytosis-associated oxidative metabolism and the killing of Candida by macrophages. J Exp Med. 1980 Jul 1;152(1):85–98. [PMC free article] [PubMed]
  • Sasada M, Kubo A, Nishimura T, Kakita T, Moriguchi T, Yamamoto K, Uchino H. Candidacidal activity of monocyte-derived human macrophages: relationship between Candida killing and oxygen radical generation by human macrophages. J Leukoc Biol. 1987 Apr;41(4):289–294. [PubMed]
  • Schneemann M, Schoedon G, Hofer S, Blau N, Guerrero L, Schaffner A. Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. J Infect Dis. 1993 Jun;167(6):1358–1363. [PubMed]
  • Shiratsuchi H, Johnson JL, Ellner JJ. Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol. 1991 May 1;146(9):3165–3170. [PubMed]
  • Trauth BC, Klas C, Peters AM, Matzku S, Möller P, Falk W, Debatin KM, Krammer PH. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989 Jul 21;245(4915):301–305. [PubMed]
  • Vaux DL. Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):786–789. [PMC free article] [PubMed]

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