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

• Published in: Journal of leukocyte biology Vol. 86; no. 1; pp. 53 - 60
• Main Authors: Patel, Naimish R., Swan, Katharine, Li, Xin, Tachado, Souvenir D., Koziel, Henry
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.07.2009; The Society for Leukocyte Biology
• Subjects: Alveoli; Apoptosis; Apoptosis - immunology; Bcl-3 protein; Data processing; Disease Susceptibility; HIV Infections - complications; Human immunodeficiency virus; Humans; Immunity, Innate; Interleukin 10; Interleukin-10 - analysis; Interleukin-10 - physiology; Leukocytes; Lung; Lung - chemistry; Macrophages; Macrophages, Alveolar - immunology; Macrophages, Alveolar - microbiology; Macrophages, Alveolar - virology; molecules; mRNA; NF-kappa B - antagonists & inhibitors; NF‐κB; Nuclear transport; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins - physiology; Spotlight on Leading Edge Research; Toll‐like receptors; transcription factors; Transcription Factors - analysis; Transcription Factors - physiology; Tuberculosis - etiology; Tuberculosis - pathology; Tuberculosis - virology; Tumor necrosis factor
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0908574

HIV alters the lung environment through increased IL‐10, leading to an impaired macrophage apoptotic response to Mycobacterium tuberculosis via upregulation of macrophage BCL‐3. 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‐α‐dependent manner. IL‐10 levels in BALF from HIV+ persons were significantly elevated 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, IκB degradation, or NF‐κB p65 nuclear translocation in response to MTb, but IL‐10 did increase levels of AM BCL‐3, an inhibitor of NF‐κB 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.