IL-17A enhances IL-13 activity by enhancing IL-13–induced signal transducer and activator of transcription 6 activation

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 2; pp. 462 - 471.e14
• Main Authors: Hall, Sara L., Baker, Theresa, Lajoie, Stephane, Richgels, Phoebe K., Yang, Yanfen, McAlees, Jaclyn W., van Lier, Adelaide, Wills-Karp, Marsha, Sivaprasad, Umasundari, Acciani, Thomas H., LeCras, Timothy D., Myers, Jocelyn Biagini, Kovacic, Melinda Butsch, Lewkowich, Ian P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017; Elsevier Limited
• Subjects: Airway management; Allergy and Immunology; Animals; Asthma; Asthma - chemically induced; Asthma - immunology; Cell Line; Cytokines; Cytokines - metabolism; Fibroblasts - immunology; Gene expression; Gene Expression Regulation; Human subjects; Humans; IL-13; IL-17A; Inflammation; Interleukin-13 - metabolism; Interleukin-13 Receptor alpha2 Subunit - genetics; Interleukin-17 - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Pathogenesis; Pathology; Pneumonia - chemically induced; Pneumonia - immunology; Proteins; Receptors, Interleukin-17 - genetics; signal transducer and activator of transcription 6; Signal Transduction; Smooth muscle; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Studies; Th2 Cells - immunology; IL-17A; signal transduction; pSTAT6; IL-13; AHR; BAL; NEC; Asthma; signal transducer and activator of transcription 6; AUC; IL-13R; PE; t1/2; cytokines; STAT6; WT; CLCA3; Phosphorylated STAT6; Bronchoalveolar lavage; Area under the curve; Half-life; Chloride channel, calcium activated 3; Wild-type; Airway hyperresponsiveness; IL-13 receptor; Phycoerythrin; Nasal epithelial cell
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.04.037

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. We sought to gain mechanistic insight into how IL-17A can influence IL-13–driven responses. 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. 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. 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. [Display omitted]