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.