title: Cooperative effects of rhinovirus and TNF-{alpha} on airway epithelial cell chemokine expression.
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-alpha, 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-alpha 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-alpha 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-alpha responses. We conclude that RV infection and TNF-alpha stimulation induce cooperative increases in epithelial cell chemokine expression, providing a cellular mechanism for RV-induced exacerbations of airways disease.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109-0688, USA.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.forename: Umadevi S
authors.initials: US
authors.lastname: Sajjan
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Nagarkar
authors.forename: Adam M
authors.initials: AM
authors.lastname: Goldsmith
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D010850:Picornaviridae Infections / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012229:Rhinovirus; D018808:Transcription Factor AP-1 / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018925:Chemokines; D019743:Chemokines, CXC; D016209:Interleukin-8; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D048049:Extracellular Signal-Regulated MAP Kinases