Author:
Newcomb Dawn C.,Sajjan Umadevi S.,Nagarkar Deepti R.,Goldsmith Adam M.,Bentley J. Kelley,Hershenson Marc B.
Abstract
Rhinovirus (RV) infections trigger exacerbations of airways disease, but underlying mechanisms remain unknown. We hypothesized that RV and cytokines present in inflamed airways combine to induce augmented airway epithelial cell chemokine expression, promoting further inflammation. To test this hypothesis in a cellular system, we examined the combined effects of RV39 and TNF-α, a cytokine increased in asthma and chronic obstructive pulmonary disease, on airway epithelial cell proinflammatory gene expression. Costimulation of 16HBE14o- human bronchial epithelial cells and primary mucociliary-differentiated tracheal epithelial cells with RV and TNF-α induced synergistic increases in IL-8 and epithelial neutrophil attractant-78 production. Similar synergism was observed for IL-8 promoter activity, demonstrating that the effect is transcriptionally mediated. Whereas increases in ICAM-1 expression and viral load were noted 16–24 h after costimulation, cooperative effects between RV39 and TNF-α were evident 4 h after stimulation and maintained despite incubation with blocking antibody to ICAM-1 given 2 h postinfection or UV irradiation of virus, implying that effects were not solely due to changes in ICAM-1 expression. Furthermore, RV39 infection induced phosphorylation of ERK and transactivation of the IL-8 promoter AP-1 site, which functions as a basal level enhancer, leading to enhanced TNF-α responses. We conclude that RV infection and TNF-α stimulation induce cooperative increases in epithelial cell chemokine expression, providing a cellular mechanism for RV-induced exacerbations of airways disease.
Publisher
American Physiological Society
Subject
Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology
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