title: Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection.
abstract: Human rhinovirus (HRV) infections are associated with exacerbations of asthma and chronic obstructive pulmonary disease that are characterized by a selective neutrophil infiltration. IL-17A, a cytokine derived primarily from activated T cells, has been linked to neutrophilic inflammation of the airways. We hypothesized that IL-17A alters the response of HRV-infected epithelial cells to modulate airway inflammatory cell populations. IL-17A synergistically enhanced HRV-16-induced epithelial production of the neutrophil chemoattractant, IL-8, as well as human beta-defensin-2 (HBD-2), a chemoattractant for immature dendritic cells and memory T cells, but suppressed viral production of the eosinophil chemoattractant, RANTES. These effects were not due to alterations of viral uptake or replication by IL-17A. The synergy between HRV-16 and IL-17A for IL-8 protein production was both dose- and time-dependent. IL-8 induction by IL-17A or HRV-16, alone and in combination, was reduced by inhibitors of the p38 and p44/42 MAPK pathways. By contrast, induction of HBD-2 depended on the activation of the p38 and JNK pathways. The ability of IL-17A to synergistically enhance HRV-induced IL-8 is mediated posttranscriptionally, since IL-8 promoter activation by the combination of the two stimuli was merely additive, whereas the combination of IL-17A and HRV-16 led to stabilization of IL-8 mRNA. Similarly, stimulation of HBD-2 promoter constructs by the combination of IL-17A and HRV-16 was no more than the sum of the individual responses. Further studies are needed to examine HBD-2 mRNA stability. Taken together, these data represent the first demonstration that IL-17A can modify epithelial responses to HRV in a manner that would be expected to favor the recruitment of neutrophils, immature dendritic cells, and memory T cells to the airways.
authors.affiliation: Airway Inflammation Group, Institute for Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Shahina
authors.initials: S
authors.lastname: Wiehler
authors.forename: David
authors.initials: D
authors.lastname: Proud
mesh_terms: D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D010850:Picornaviridae Infections / Q000188:drug therapy / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology / Q000821:virology; D011401:Promoter Regions, Genetic / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D012229:Rhinovirus / Q000254:growth & development / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000276:immunology; D023083:beta-Defensins / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; C106641:DEFB4A protein, human; D004791:Enzyme Inhibitors; C508717:IL17A protein, human; D020381:Interleukin-17; D016209:Interleukin-8; D023083:beta-Defensins