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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0908574

Received for publication September 26, 2008.
Revised March 3, 2009.
Accepted for publication March 4, 2009.

Article

Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: potential role of IL-10 and BCL-3

Naimish R. Patel @, Katharine Swan , Xin Li , Souvenir D. Tachado , and Henry Koziel

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

@ To whom correspondence should be addressed. E-mail: npatel{at}bidmc.harvard.edu.


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Abstract

The mechanism of increased MTb disease susceptibility in HIV+ persons remains poorly understood. Apoptosis of macrophages in response to MTb represents a critical host defense response, and decreased apoptosis may represent a mechanism of increased susceptibility to MTb in HIV. In the current study, MTb-mediated apoptosis of human AM was reduced in HIV+ subjects compared with healthy subjects in a TNF-{alpha}-dependent manner. IL-10 levels in BALF from HIV+ persons were elevated significantly compared with HIV– persons, and exogenous IL-10 reduced MTb-mediated apoptosis in healthy AM, suggesting that IL-10 could mediate decreased apoptosis observed in HIV. Further study showed that IL-10 reduced TNF release in response to MTb in AM through a reduction in TNF mRNA levels, and exogenous TNF could partially reverse IL-10-associated effects on AM apoptosis. IL-10 did not influence p-IRAK, I{kappa}B degradation, or NF-{kappa}B p65 nuclear translocation in response to MTb, but IL-10 did increase levels of AM BCL-3, an inhibitor of NF-{kappa}B nuclear activity. BCL-3 knockdown in human macrophages increased MTb-mediated TNF release. Importantly, BCL-3 levels in AM from HIV+ subjects were higher compared with healthy subjects. Taken together, these data suggest that elevated lung levels of IL-10 may impair MTb-mediated AM apoptosis in HIV through a BCL-3-dependent mechanism. BCL-3 may represent a potential therapeutic target to treat or prevent MTb disease in HIV+ persons.

Key Words: Toll-like receptors • molecules • transcription factors • NF-{kappa}B


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A. Lalvani and S. Hingley-Wilson
Editorial: Live or let die--does HIV exacerbate tuberculosis by attenuating M. tuberculosis-induced apoptosis?
J. Leukoc. Biol., July 1, 2009; 86(1): 9 - 11.
[Full Text] [PDF]