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Title: Ikkepsilon regulates viral-induced interferon regulatory factor-3 activation via a redox-sensitive pathway.

Authors: Indukuri, Hemalatha; Castro, Shawn M; Liao, Sha-Mei; Feeney, Lee Ann; Dorsch, Marion; Coyle, Anthony J; Garofalo, Roberto P; Brasier, Allan R; Casola, Antonella

Published In Virology, (2006 Sep 15)

Abstract: Respiratory syncytial virus (RSV)-induced chemokine gene expression occurs through the activation of a subset of transcription factors, including Interferon Regulatory Factor (IRF)-3. In this study, we have investigated the signaling pathway leading to RSV-induced IRF-3 activation and whether it is mediated by intracellular reactive oxygen species (ROS) generation. Our results show that RSV infection induces expression and catalytic activity of IKKepsilon, a noncanonical IKK-like kinase. Expression of a kinase-inactive IKKepsilon blocks RSV-induced IRF-3 serine phosphorylation, nuclear translocation and DNA-binding, leading to inhibition of RANTES gene transcription, mRNA expression and protein synthesis. Treatment of alveolar epithelial cells with antioxidants or with NAD(P)H oxidase inhibitors abrogates RSV-induced chemokine secretion, IRF-3 phosphorylation and IKKepsilon induction, indicating that ROS generation plays a fundamental role in the signaling pathway leading to IRF-3 activation, therefore, identifying a novel molecular target for the development of strategies aimed to modify the inflammatory response associated with RSV infection of the lung.

PubMed ID: 16806387 Exiting the NIEHS site

MeSH Terms: Cell Line, Tumor; Epithelial Cells/metabolism; Epithelial Cells/virology; Gene Expression Regulation, Viral*; Humans; I-kappa B Kinase/metabolism*; Interferon Regulatory Factor-3/metabolism*; Lung Neoplasms/pathology; Oxidation-Reduction; Phosphorylation; RANTES/analysis; RNA, Messenger/analysis; Reactive Oxygen Species/metabolism; Respiratory Syncytial Virus Infections/virology; Respiratory Syncytial Viruses/physiology; Signal Transduction

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