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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 IKKε, a noncanonical IKK-like kinase. Expression of a kinase-inactive IKKε 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 IKKε 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.

Original languageEnglish (US)
Pages (from-to)155-165
Number of pages11
JournalVirology
Volume353
Issue number1
DOIs
StatePublished - Sep 15 2006

Keywords

  • Airway epithelial cells
  • IRF
  • Inflammation
  • ROS
  • RSV

ASJC Scopus subject areas

  • Virology

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