Mammalian target of rapamycin inhibition in macrophages of asymptomatic HIV+ persons reverses the decrease in TLR-4-mediated TNF-α release through prolongation of MAPK pathway activation.
Mammalian target of rapamycin inhibition in macrophages of asymptomatic HIV+ persons reverses the decrease in TLR-4-mediated TNF-α release through prolongation of MAPK pathway activation.
复制标题
DOI：
10.4049/jimmunol.1101532
复制
发表时间：
2011-12-01
期刊：
影响因子：
--
通讯作者：
Tachado SD
中科院分区：
文献类型：
--
作者：
Li X;Han X;Llano J;Bole M;Zhou X;Swan K;Anandaiah A;Nelson B;Patel NR;Reinach PS;Koziel H;Tachado SD
Toll 样受体 4 (TLR4) 介导的信号传导在 HIV+ 患者的巨噬细胞中显着受损，这主要是由于 PI3K 的组成性激活导致 MyD88 依赖性途径信号传导的改变。在这里，我们在这些巨噬细胞中评估了脂质 A 诱导的 TLR4 介导的 TNFα 释放的减弱是否与 PI3K 诱导的哺乳动物雷帕霉素靶点 (mTOR) 活性上调相关。雷帕霉素抑制 mTOR 增强了 TLR4 介导的 TNFα 释放，但抑制了抗炎 IL-10 的释放。巨噬细胞中 mTOR 的靶向基因沉默导致脂质 A 诱导的 TNFα 和 IL-10 释放模式与雷帕霉素诱导的释放模式相似。雷帕霉素以剂量依赖性方式恢复 MyD88-IRAK 相互作用。 MyD88 (shRNA) 和 mTOR (RNAi) 抑制的靶向基因沉默导致 TLR4 介导的 p70s6K 激活并增强 TNFα 释放，而沉默和非沉默的 HIV+ 巨噬细胞中 IL-10 的释放均受到抑制。此外，mTOR 抑制通过增强和延长 ERK1/2 和 JNK1/2 MAP 激酶的磷酸化来增强脂质 A 诱导的 TNFα 释放，这与时间依赖性 MKP-1 不稳定相关。总而言之，HIV+巨噬细胞中 TLR4 介导的 TNFα 释放受损部分归因于 MyD88 依赖性信号通路中组成型 PI3K 表达导致的 mTOR 激活。这些变化导致 MKP-1 稳定，从而缩短并减弱 MAP 激酶的激活。 mTOR 抑制可能作为上调 HIV+ 人群巨噬细胞先天免疫宿主防御反应的潜在治疗靶点。
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.
登录
查看更多内容
DOI：
10.1016/s0006-291x(03)00301-2
发表时间：
2003-03-28
影响因子：
3.1
作者：
Stawowy, P;Goetze, S;Graf, K
通讯作者：
Graf, K
DOI：
10.1084/jem.20071728
发表时间：
2008-06-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cao W;Bao C;Padalko E;Lowenstein CJ
通讯作者：
Lowenstein CJ
影响因子：
32.4
作者：
Blanchet FP;Moris A;Nikolic DS;Lehmann M;Cardinaud S;Stalder R;Garcia E;Dinkins C;Leuba F;Wu L;Schwartz O;Deretic V;Piguet V
通讯作者：
Piguet V
影响因子：
5.4
作者：
Nicol, Marlynne Q.;Mathys, Jean-Marie;Skolnik, Paul R.
通讯作者：
Skolnik, Paul R.
影响因子：
56.9
作者：
Brondello, JM;Pouysségur, J;McKenzie, FR
通讯作者：
McKenzie, FR