Background: Increased IL-17A production has been associated with more severe asthma; however, the mechanisms whereby IL-17A can contribute to IL-13-driven pathology in asthmatic patients remain unclear.
Objective: We sought to gain mechanistic insight into how IL-17A can influence IL-13-driven responses.
Methods: The effect of IL-17A on IL-13-induced airway hyperresponsiveness, gene expression, mucus hypersecretion, and airway inflammation was assessed by using in vivo models of IL-13-induced lung pathology and in vitro culture of murine fibroblast cell lines and primary fibroblasts and human epithelial cell lines or primary human epithelial cells exposed to IL-13, IL-17A, or both.
Results: Compared with mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A had augmented airway hyperresponsiveness, mucus production, airway inflammation, and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, coexposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, the IL-17A-driven increase in IL-13-induced gene expression was associated with enhanced IL-13-driven signal transducer and activator of transcription 6 activation.
Conclusions: Our data suggest that IL-17A contributes to asthma pathophysiology by increasing the capacity of IL-13 to activate intracellular signaling pathways, such as signal transducer and activator of transcription 6. These data represent the first mechanistic explanation of how IL-17A can directly contribute to the pathogenesis of IL-13-driven pathology.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149451 | PMC |
http://dx.doi.org/10.1016/j.jaci.2016.04.037 | DOI Listing |
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!