Associations Between Asthma Severity and Responsiveness to Th2- and Th17-derived Cytokines in Pediatric Asthmatics

RATIONALE: Mild and moderate allergic asthma are characterized by airway eosinophilia, airway hyperresponsiveness and a maladaptive Th2 response to aeroallergens, which is typically well controlled with steroids. Severe steroid refractory asthma is often associated with neutrophilic inflammation, elevated Th17 cell numbers and IL-17A. A mouse model of allergen-driven severe asthma supports an association between Th17 responses and severe disease, and demonstrate that severely asthmatic animals have increased production of Th17 cytokines and responsiveness to IL-17A. We hypothesize that similar associations between asthma severity and production of, or responsiveness to, Th17 cytokines is observed in asthmatic children.

METHODS: Nasal epithelial cells were collected from well-characterized pediatric asthmatics cohort. The cells were cultured and exposed to IL-13 and IL-17A to determine cellular responsiveness of a relevant primary cell type. Western blot analysis of STAT6 phosphorylation was used to measure IL-13 responses and ELISA analysis of CXCL1 production was used to measure IL-17A responses.

RESULTS: IL-13-induced phospho-STAT6 and IL-17A-induced CXCL1 production in nasal epithelial cells increases with asthma severity. The link between asthma severity and IL-13 responsiveness is more pronounced in males. IL-17A weakly augments IL-13-mediated phospho-STAT6 in mild and severe asthmatics and more strongly in moderate asthmatics. IL-13 suppresses IL-17A-mediated CXCL1 production.

CONCLUSIONS: Nasal epithelial cells responses to IL-13 and IL-17A vary proportionally with allergic asthma severity, suggesting that severity can be regulated at the level of cytokine responsiveness. Moreover, IL-17A augments IL-13-mediated responses while IL-13 suppresses IL-17A-mediated responses, providing a potential mechanistic explanation for increased susceptibility to bacterial and viral infections in allergic individuals.