Reactive oxygen species mediate virus-induced STAT activation

Role of tyrosine phosphatases

Tianshuang Liu, Shawn Castro, Allan R. Brasier, Mohammad Jamaluddin, Roberto Garofalo, Antonella Casola

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Respiratory syncytial virus (RSV) is the leading cause of epidemic respiratory tract illness in children in the United States and worldwide. RSV infection of airway epithelial cells induces formation of reactive oxygen species (ROS), whose production mediates the expression of cytokines and chemokines involved the immune/inflammatory responses of the lung. In this study, we have investigated the role of ROS in RSV-induced signal transducers and activators of transcription (STAT) activation and interferon regulatory factor (IRF) gene expression in human airway epithelial cells. Our results indicate that RSV replication induces IRF-1 and -7 gene transcription, a response abrogated by antioxidants. RSV infection induces binding of STAT to the IRF-1 γ-interferon-activated sequence (GAS) and IRF-7 interferon-stimulated responsive element (ISRE). STAT1 and STAT3 bind IRF-1 GAS, whereas STAT1, STAT2, IRF-1, and IRF-9 bind IRF-7 ISRE. Antioxidant treatment blocks RSV-induced STAT binding to both the IRF-1 GAS and IRF-7 ISRE by inhibition of inducible STAT1 and STAT3 tyrosine phosphorylation, suggesting that RSV-induced ROS formation is required for STAT activation and IRF gene expression. Although protein tyrosine phosphorylation is necessary for RSV-induced STAT activation, Janus kinase and Src kinase activation do not mediate this effect. Instead, RSV infection inhibits intracellular tyrosine phosphatase activity, which is restored by antioxidant treatment. Pharmacological inhibition of tyrosine phosphatases induces STAT activation. Together, these results suggest that modulation of phosphatases could be an important mechanism of virus-induced STAT activation. Treatment of alveolar epithelial cells with the NAD(P)H oxidase inhibitor diphenylene iodonium abolishes RSV-induced STAT activation, indicating that NAD(P)H oxidase-produced ROS are required for downstream activation of the transcription factors IRF and STAT in virus-infected airway epithelial cells.

Original languageEnglish (US)
Pages (from-to)2461-2469
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number4
DOIs
StatePublished - Jan 23 2004

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Transcription
Transducers
Viruses
Phosphoric Monoester Hydrolases
Transcriptional Activation
Respiratory Syncytial Viruses
Tyrosine
Reactive Oxygen Species
Interferon Regulatory Factor-1
Interferon Regulatory Factor-7
Chemical activation
Interferon Regulatory Factors
Respiratory Syncytial Virus Infections
Interferons
Antioxidants
NADPH Oxidase
Epithelial Cells
Regulator Genes
Gamma Subunit Interferon-Stimulated Gene Factor 3
Phosphorylation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Reactive oxygen species mediate virus-induced STAT activation : Role of tyrosine phosphatases. / Liu, Tianshuang; Castro, Shawn; Brasier, Allan R.; Jamaluddin, Mohammad; Garofalo, Roberto; Casola, Antonella.

In: Journal of Biological Chemistry, Vol. 279, No. 4, 23.01.2004, p. 2461-2469.

Research output: Contribution to journalArticle

Liu, Tianshuang ; Castro, Shawn ; Brasier, Allan R. ; Jamaluddin, Mohammad ; Garofalo, Roberto ; Casola, Antonella. / Reactive oxygen species mediate virus-induced STAT activation : Role of tyrosine phosphatases. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 4. pp. 2461-2469.
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