Ikkepsilon regulates viral-induced interferon regulatory factor-3 activation via a redox-sensitive pathway.
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.
Indukuri
Hemalatha
H
Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555-0366, USA.
Castro
Shawn M
SM
Liao
Sha-Mei
SM
Feeney
Lee Ann
LA
Dorsch
Marion
M
Coyle
Anthony J
AJ
Garofalo
Roberto P
RP
Brasier
Allan R
AR
Casola
Antonella
A
D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000032:analysis; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000502:physiology; D015398:Signal Transduction
D018946:Chemokine CCL5; D050838:Interferon Regulatory Factor-3; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051550:I-kappa B Kinase