Dual role of NOX2 in respiratory syncytial virus- and Sendai virus-induced activation of NF-κB in airway epithelial cells
Dual role of NOX2 in respiratory syncytial virus- and Sendai virus-induced activation of NF-κB in airway epithelial cells
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DOI：
10.4049/jimmunol.180.10.6911
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发表时间：
2008-05-15
影响因子：
4.4
通讯作者：
Grandvaux, Nathalie
中科院分区：
文献类型：
--
作者：
Fink, Karin;Duval, Annick;Grandvaux, Nathalie
人呼吸道合胞病毒(RSV)是副粘病毒科的成员之一，是世界范围内引起儿童呼吸道疾病的最重要的病原体。呼吸道上皮细胞(AEC)是呼吸道合胞病毒(RSV)的主要靶点。AEC负责分泌广泛的细胞因子和趋化因子，这些细胞因子和趋化因子是宿主在应对RSV感染时引发的加重呼吸道炎症的重要介质。核因子-kappaB是一个关键的转录因子，负责调节细胞因子和趋化因子的基因表达，因此是一个潜在的治疗靶点。在本研究中，我们试图描述RSV诱导的活性氧在调节导致核因子-kappaB激活的信号通路中的作用。首先，我们证明，除了已有的I kappa Bα依赖途径外，P65在Ser(536)处的磷酸化是调节A549细胞中RsV激活NF-kappa B的一个重要事件。利用抗氧化剂和RNA干扰策略，我们证明了含有NADPH氧化酶2(NOX2)的NADPH氧化酶是RSV诱导的NF-kappa B激活的重要调节因子。分子分析表明，在A549和正常人的支气管上皮细胞中，NOX2作用于Ikappa BαSer(32)和p65 Ser(536)磷酸化的上游。在仙台病毒感染的情况下也得到了类似的结果，从而证明了新发现的依赖于NOX2的NF-kappa B激活途径并不局限于副粘病毒科中的RSV。这些结果说明了先前未知的NOX2在调节核因子-kappa B以响应RSV和仙台病毒非人道AEC中的双重作用。
Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is the most important viral agent of pediatric respiratory tract disease worldwide. Human airway epithelial cells (AEC) are the primary targets of RSV. AEC are responsible for the secretion of a wide spectrum of cytokines and chemokines that are important mediators of the exacerbated airway inflammation triggered by the host in response to RSV infection. NF-kappa B is a key transcription factor responsible for the regulation of cytokine and chemokine gene expression and thus represents a potential therapeutic target. In the present study, we sought to delineate the role of RSV-induced reactive oxygen species in the regulation of the signaling pathways leading to NF-kappa B activation. First, we demonstrate that besides the well-characterized I kappa B alpha-dependent pathway, phosphorylation of p65 at Ser(536) is an essential event regulating NF-kappa B activation in response to RSV in A549. Using antioxidant and RNA-interference strategies, we show that a NADPH oxidase 2 (NOX2)-containing NADPH oxidase is an essential regulator of RSV-induced NF-kappa B activation. Molecular analyses revealed that NOX2 acts upstream of both the phosphorylation of I kappa B alpha at Ser(32) and of p65 at Ser(536) in A549 and normal human bronchial epithelial cells. Similar results were obtained in the context of infection by Sendai virus, thus demonstrating that the newly identified NOX2-dependent NF-kappa B activation pathway is not restricted to RSV among the Paramyxoviridae. These results illustrate a previously unrecognized dual role of NOX2 in the regulation of NF-kappa B in response to RSV and Sendai virus inhuman AEC.