and BCL-3

The mechanism of increased MTb disease susceptibil-ity in HIV persons remains poorly understood. Apopto-sis of macrophages in response to MTb represents a critical host defense response, and decreased apopto-sis may represent a mechanism of increased suscepti-bility 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--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 de-creased 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-asso-ciated effects on AM apoptosis. IL-10 did not influence p-IRAK, IB degradation, or NF-B p65 nuclear translo-cation in response to MTb, but IL-10 did increase levels of AM BCL-3, an inhibitor of NF-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-medi-ated AM apoptosis in HIV through a BCL-3-dependent mechanism. BCL-3 may represent a potential thera-peutic target to treat or prevent MTb disease in HIV persons. J. Leukoc. Biol. 86: 000–000; 2009