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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Synergistic activation of NF-κB by nontypeable Haemophilus influenzae and tumor necrosis factor α
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Synergistic activation of NF-κB by nontypeable Haemophilus influenzae and tumor necrosis factor α

机译：非分型流感嗜血杆菌与肿瘤坏死因子α协同激活NF-κB

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摘要

Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing otitis media in children and exacerbation of chronic obstructive pulmonary disease in adults. Like most other bacterial infections, NTHi infections are also characterized by inflammation, which is mainly mediated by cytokines and chemo-kines such as tumor necrosis factor α (TNF-α). Among a variety of transcription regulators, NF-κB has been shown to play a critical role in regulating the expression of large numbers of genes encoding inflammatory mediators. In review of the current studies on NF-κB regulation, most of them have focused on investigating how NF-κB is activated by a single inducer at a time. However, in bacteria-induced inflammation in vivo, multiple inducers including both exogenous and endogenous mediators are present simultaneously. A key issue that has yet to be addressed is whether the exogenous inducers such as NTHi and the endogenous factors such as TNF-αactivate NF-κB in a synergistic manner. We show that NTHi and TNF-α, when present together, synergistically induce NF-κB activation via two distinct signaling pathways: NF-κB transloca-tion-dependent and -independent pathways. The NF-κB transloca-tion-dependent pathway involves NF-κB-inducing kinase-IκB ki-nase β/γ-dependent phosphorylation and degradation of IκBα, whereas the NF-κB translocation-independent pathway involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase kinase 1-dependent activation of MAPK kinase 3/6-p38 MAPK pathway. In addition, the same signaling pathways are also involved in synergistic induction of TNF-α, IL-1β, and IL-8. These studies should deepen our understanding of the molecular mechanisms underlying the combinatorial regulation of inflammation and lead to development of therapeutic strategies for NTHi-induced infections.
机译：非分型流感嗜血杆菌（NTHi）是一种重要的人类病原体，可引起儿童中耳炎和成人慢性阻塞性肺疾病的恶化。像大多数其他细菌感染一样，NTHi感染也具有炎症特征，主要由细胞因子和化学因子（例如肿瘤坏死因子α（TNF-α））介导。在多种转录调节剂中，已证明NF-κB在调节大量编码炎症介质的基因的表达中起关键作用。在对目前有关NF-κB调节的研究进行回顾时，大多数研究集中在研究一次单个诱导物如何激活NF-κB。然而，在体内细菌诱导的炎症中，同时存在多种诱导剂，包括外源性和内源性介质。尚未解决的关键问题是外源性诱导物（例如NTHi）和内源性因子（例如TNF-α）是否以协同方式激活NF-κB。我们显示，NTHi和TNF-α一起存在时，可通过两个不同的信号传导途径协同诱导NF-κB活化：NF-κB转运依赖和非依赖性途径。 NF-κB易位依赖途径涉及NF-κB诱导激酶-IκB激酶β/γ依赖的磷酸化和IκBα降解，而NF-κB易位依赖途径涉及有丝分裂原激活的蛋白激酶（MAPK ）/细胞外信号调节激酶激酶激酶1依赖的MAPK激酶3 / 6-p38 MAPK途径的激活。另外，相同的信号传导途径也参与TNF-α，IL-1β和IL-8的协同诱导。这些研究应加深我们对炎症的组合调节的分子机制的了解，并导致NTHi诱导的感染的治疗策略的发展。

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