ToxSci Advance Access originally published online on August 22, 2008
Toxicological Sciences 2008 106(2):509-518; doi:10.1093/toxsci/kfn175
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Cigarette Smoke Condensate Enhances Respiratory Syncytial Virus–Induced Chemokine Release by Modulating NF-kappa B and Interferon Regulatory Factor Activation
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* Department of Pharmacology and Toxicology
Department of Pediatrics, Microbiology
Immunology
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas 77555
1 To whom correspondence should be addressed at Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0366. Fax: (409) 772-1761. E-mail: ancasola{at}utmb.edu.
Received April 25, 2008; accepted August 18, 2008
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Abstract |
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Exposure to cigarette smoke is a risk factor contributing to the severity of respiratory tract infections associated with respiratory syncytial virus (RSV). Stimulation of airway epithelial cells by either RSV or cigarette smoke condensate (CSC) has been shown to induce secretion of the proinflammatory chemokines. However, the effect of coexposure of airway epithelial cells to CSC and RSV on inducible chemokine production has not been previously investigated. The results of this study indicate that CSC costimulation significantly increased RSV-induced interleukin-8 (IL-8) and monocyte chemoattactant protein-1 gene and protein expression when compared with each stimulus alone. Promoter deletion studies identified the interferon stimulatory response element (ISRE) of the IL-8 promoter as a critical region responsible for the synergistic increase of IL-8 gene transcription during mixed exposure. CSC costimulation enhanced RSV-induced activation of interferon regulatory factor (IRF)-1 and IRF-7, which bind to the ISRE site. CSC also furthered RSV-induced activation of the transcription factor nuclear factor kappa B (NF-
B), as shown by increased NF-B DNA binding to its specific site of the IL-8 promoter and increased NF-B–driven gene transcription. Therefore, our data demonstrate that a combined exposure to CSC and RSV synergistically increases chemokine expression in airway epithelial cells, suggesting that CSC contributes to an exuberant immune response to RSV by stimulating overlapping signal transduction pathways.
Key Words: RSV; cigarette smoke condensate; chemokines; IRF; NF-B.