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

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

doi:10.1016/j.virol.2006.05.022

PubMed · 16806387

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

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

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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.

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Cell Line, Tumor Chemokine CCL5 Epithelial Cells Gene Expression Regulation, Viral Humans I-kappa B Kinase Interferon Regulatory Factor-3 Lung Neoplasms Oxidation-Reduction Phosphorylation RNA, Messenger Reactive Oxygen Species Respiratory Syncytial Virus Infections Respiratory Syncytial Viruses Signal Transduction Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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Hemalatha Indukuri, Shawn M Castro, Sha-Mei Liao, Lee Ann Feeney, Marion Dorsch, Anthony J Coyle, Roberto P Garofalo, Allan R Brasier, Antonella Casola. 2006-06-27. Ikkepsilon regulates viral-induced interferon regulatory factor-3 activation via a redox-sensitive pathway.. https://doi.org/10.1016/j.virol.2006.05.022

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