Oxidant tone regulates RANTES gene expression in airway epithelial cells infected with respiratory syncytial virus. Role in viral-induced interferon regulatory factor activation.
Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part, through its ability to induce chemokine synthesis in infected airway epithelial cells. RANTES (regulated upon activation, normal T-cells expressed and secreted) is a CC chemokine which recruits and activates monocytes, lymphocytes, and eosinophils, all cell types present in the lung inflammatory infiltrate induced by RSV infection. In this study we investigated the role of reactive oxygen species in the induction of RANTES gene expression in human type II alveolar epithelial cells (A549), following RSV infection. Our results indicate that RSV infection of airway epithelial cells rapidly induces reactive oxygen species production, prior to RANTES expression, as measured by oxidation of 2',7'-dichlorofluorescein. Pretreatment of airway epithelial cells with the antioxidant butylated hydroxyanisol (BHA), as well a panel of chemically unrelated antioxidants, blocks RSV-induced RANTES gene expression and protein secretion. This effect is mediated through the ability of BHA to inhibit RSV-induced interferon regulatory factor binding to the RANTES promoter interferon-stimulated responsive element, that is absolutely required for inducible RANTES promoter activation. BHA inhibits de novo interferon regulator factor (IRF)-1 and -7 gene expression and protein synthesis, and IRF-3 nuclear translocation. Together, these data indicates that a redox-sensitive pathway is involved in RSV-induced IRF activation, an event necessary for RANTES gene expression.
Casola
A
A
Departments of Pediatrics, Internal Medicine, Sealy Center for Molecular Sciences, Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-0366, USA.
Burger
N
N
Liu
T
T
Jamaluddin
M
M
Brasier
A R
AR
Garofalo
R P
RP
D001483:Base Sequence; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D018946:Chemokine CCL5 / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006801:Humans; D050835:Interferon Regulatory Factors; D016877:Oxidants / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D014132:Trachea / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D014157:Transcription Factors / Q000378:metabolism*; D014764:Viral Proteins
D018946:Chemokine CCL5; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016877:Oxidants; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D002083:Butylated Hydroxyanisole