Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: potential role of IL-10 and 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-alpha-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, IkappaB degradation, or NF-kappaB p65 nuclear translocation in response to MTb, but IL-10 did increase levels of AM BCL-3, an inhibitor of NF-kappaB 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.
Patel
Naimish R
NR
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. npatel@bidmc.harvard.edu
Swan
Katharine
K
Li
Xin
X
Tachado
Souvenir D
SD
Koziel
Henry
H
D017209:Apoptosis / Q000276:immunology*; D000081242:B-Cell Lymphoma 3 Protein; D004198:Disease Susceptibility; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000032:analysis / Q000502:physiology*; D008168:Lung / Q000737:chemistry; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology* / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014376:Tuberculosis / Q000209:etiology* / Q000473:pathology / Q000821:virology
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016753:Interleukin-10