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B in Airway Epithelial Cells1
* Centre Hospitalier de l’Université de Montréal Research Center- St.-Luc Hospital and Institut National de la Santé et de la Recherche Médicale Unité 743, Montreal, Quebec, Canada; and
Department of Biochemistry, Faculty of Medicine, University of Montreal, Quebec, Canada
Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is the most important viral agent of pediatric respiratory tract disease worldwide. Human airway epithelial cells (AEC) are the primary targets of RSV. AEC are responsible for the secretion of a wide spectrum of cytokines and chemokines that are important mediators of the exacerbated airway inflammation triggered by the host in response to RSV infection. NF-
B is a key transcription factor responsible for the regulation of cytokine and chemokine gene expression and thus represents a potential therapeutic target. In the present study, we sought to delineate the role of RSV-induced reactive oxygen species in the regulation of the signaling pathways leading to NF-B activation. First, we demonstrate that besides the well-characterized IB
-dependent pathway, phosphorylation of p65 at Ser536 is an essential event regulating NF-B activation in response to RSV in A549. Using antioxidant and RNA-interference strategies, we show that a NADPH oxidase 2 (NOX2)-containing NADPH oxidase is an essential regulator of RSV-induced NF-B activation. Molecular analyses revealed that NOX2 acts upstream of both the phosphorylation of IB at Ser32 and of p65 at Ser536 in A549 and normal human bronchial epithelial cells. Similar results were obtained in the context of infection by Sendai virus, thus demonstrating that the newly identified NOX2-dependent NF-B activation pathway is not restricted to RSV among the Paramyxoviridae. These results illustrate a previously unrecognized dual role of NOX2 in the regulation of NF-B in response to RSV and Sendai virus in human AEC.
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1 This work was supported by grants from the Canadian Institutes of Health Research and Fonds de la Recherche en Santé du Québec (to N.G.). K.F. and A.S.-F. were recipients of a studentship from Institut National de la Santé et de la Recherche Médicale Unité 743. N.G. was a recipient of a Tier II Canada Research Chair.
2 Address correspondence and reprint requests to Dr. Nathalie Grandvaux, Centre de Recherche du Centre Hospitalier de l’Université de Montréal-Hôpital St. Luc, 264 René Levesque-Est, PEA 311, Montréal, Quebec, Canada, H2X 1P1. E-mail address: nathalie.grandvaux{at}umontreal.ca
3 Abbreviations used in this paper: RSV, respiratory syncytial virus; AEC, airway epithelial cell; IKK, IB kinase; ROS, reactive oxygen species; BHA, butylated hydroxyanisol; NAC, N-acetylcysteine; SeV, Sendai virus; DPI, diphenyleneiodonium; RNAi, RNA interference; MOI, multiplicity of infection; NHBE, normal human bronchial epithelial cell; WCE, whole cell extract; Ct, cycle threshold; hpi, hour postinfection; Ang, angiotensin; NOX2, NADPH oxidase 2; HI-FBS, heat-inactivated FBS.
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