Submitted on February 13, 2007
Accepted on July 10, 2007
Cooperative Effects of Rhinovirus and TNF-
on Airway Epithelial Cell Chemokine Expression
Dawn C. Newcomb1, Umadevi S Sajjan2, Deepti R. Nagarkar2, Adam M. Goldsmith2, J Kelley Bentley2, and Marc B Hershenson3*
1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
2 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, United States
3 Departments of Pediatrics and Communicable Diseases, Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
* To whom correspondence should be addressed. E-mail: mhershen{at}umich.edu.
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-
, a cytokine increased in asthma and chronic obstructive pulmonary disease, on airway epithelial cell pro-inflammatory gene expression. Co-stimulation of 16HBE14o- human bronchial epithelial cells and primary mucociliary-differentiated tracheal epithelial cells with RV and TNF- 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. While increases in ICAM-1 expression and viral load were noted 16-24 h after co-stimulation, cooperative effects between RV39 and TNF- were evident 4 h after stimulation and maintained despite incubation with blocking antibody to ICAM-1 given 2 h post-infection or UV-irradiation of virus, implying that effects were not solely due to changes in ICAM-1 expression. Further, 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- responses. We conclude that RV infection and TNF- stimulation induce cooperative increases in epithelial cell chemokine expression, providing a cellular mechanism for RV-induced exacerbations of airways disease.
