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...

Toll-like receptor 4 (TLR4) mediated signaling is significantly impaired in macrophages from HIV+ persons predominantly due to altered MyD88-dependent pathway signaling caused in part by constitutive activation of PI3K. Here we assessed in these macrophages if the blunted increase in TLR4-mediated TNFα release induced by lipid A are associated with PI3K-induced upregulation of mammalian target of rapamycin (mTOR) activity. mTOR inhibition with rapamycin enhanced TLR4-mediated TNFα release, but instead suppressed anti-inflammatory IL-10 release. Targeted gene silencing of mTOR in macrophages resulted in lipid A-induced TNFα and IL-10 release patterns similar to those induced by rapamycin. Rapamycin restored MyD88-IRAK interaction in a dose-dependent manner. Targeted gene silencing of MyD88 (shRNA) and mTOR (RNAi) inhibition resulted in TLR4-mediated p70s6K activation and enhanced TNFα release, whereas IL-10 release was inhibited in both silenced and non-silenced HIV+ macrophages. Furthermore, mTOR inhibition augmented lipid A-induced TNFα release through enhanced and prolonged phosphorylation of ERK1/2 and JNK1/2 MAP kinases, which was associated with time-dependent MKP-1 destabilization. Taken together, impaired TLR4-mediated TNFα release in HIV+ macrophages is attributable in part to mTOR activation by constitutive PI3K expression in a MyD88-dependent signaling pathway. These changes result in MKP-1 stabilization, which shortens and blunts MAP kinase activation. mTOR inhibition may serve as a potential therapeutic target to upregulate macrophage innate immune host defense responsiveness in HIV+ persons.

This integrative literature review focused on the use of omega-3 fatty acid supplementation for the treatment of Crohn's disease (CD). A systematic review of studies investigating the use of omega-3 in individuals with CD was performed. OVID MEDLINE, the Cochrane Database, and CINAHL were searched for pertinent research. Experiments were limited to double-blind placebo controlled trials. Five studies observing CD relapse rates and three studies examining biochemical changes were evaluated. The studies reviewed show contradicting information regarding the efficacy of omega-3 for CD. While some studies have shown supplementation with omega-3 results in sustained remission from disease, other studies concluded no correlation between omega-3 supplementation and improved remission rates. Studies investigating biochemical variables suggest favorable changes in immunological milieu, including modifications of lipid profiles and cytokine production. The studies reviewed are adversely limited by low number of participants, short duration of study and other significant deficits. Limited data remain available and current literature indicated mixed conclusions regarding the efficacy of omega-3 for treatment of CD. Further large-scale studies of longer duration are necessary.

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