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.

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IntroductionBacterial pneumonia remains a frequent and serious complication in asymptomatic HIV ϩ persons, despite relatively preserved peripheral blood CD4 ϩ T-lymphocyte counts 1 and use of highly active antiretroviral therapy (HAART) with undetectable plasma viral loads. 2 These persons have up to 25-fold greater risk of bacterial pneumonia than their healthy cohorts. 3 However, the mechanism contributing to this increased risk is not well understood. Toll-like receptor 4 (TLR4) represents a critical pattern recognition receptor in the innate immune host cell response to bacterial infection. Functional deficiency or genetic deletion of TLR 4 increases susceptibility to Haemophilus influenza, Streptococcus pneumoniae, and Klebsiella pneumoniae respiratory tract infections in murine models. 4,5 Another indication of its importance is that TLR4 polymorphisms are associated with increased susceptibility to lung infection. 6 Our laboratory has reported impaired TLR4-mediated tumor necrosis factor ␣ (TNF␣) release in alveolar macrophages from asymptomatic HIV ϩ persons at increased clinical risk of bacterial pneumonia. 7 Increased susceptibility may be in part related to reduced alveolar macrophage extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase phosphorylation attributed to elevated MAP kinase phosphatase 1 (MKP-1) activity, 7 and constitutive phosphoinositol-3 kinase (PI3K) activation and heightened PI3K signaling in response to TLR4 activation. 8 These data suggest that the host cell proinflammatory cytokine may be suboptimal in the lungs of HIV ϩ persons and may in part contribute to increased bacterial pneumonia susceptibility and pathogenesis.TLR4 is the most studied of the TLR family of innate receptors. 9 It is a unique member of the TLR family of mammalian receptors in that TLR4 is capable of both adaptor molecule myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling. 10-12 TLR4-mediated MyD88-dependent recognition of bacterial cell wall occurs at the cell surface, 11,13 does not require receptor internalization, 11 involves interleukin-1 receptorassociated kinase (IRAK) phosphorylation, and activation of TNF receptor-associated factor 6 (TRAF6), nuclear factor-B (NF-B), and MAP kinases (such as ERK1/2, p38, and Jun kinase), with the subsequent release of proinflammatory cytokines such as TNF␣ 14 that may contribute to an effective host defense response to bacteria. In contrast, TLR4-mediated MyD88-independent signaling requires receptor internalization and is mediated through Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-␤ (IFN␤; TRIF), 11 involves activation of IFN regulatory factor 3 (IRF3) and STAT1 15 with release of type-1 IFNs, 16 IL-10, 15 RANTES 15 and may be involved in antiviral host defense. 17 Recent work in our laboratory has shown impaired TLR4-mediated signaling response in alveolar macrophages from asymptomatic HIV ϩ persons at high clinical risk of bacterial pneumonia. 7,8 However, whe...