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

Sara L. Hall, Theresa Baker, Stephane Lajoie, Phoebe K. Richgels, Yanfen Yang, Jaclyn W. McAlees, Adelaide van Lier, Marsha Wills-Karp, Umasundari Sivaprasad, Thomas H. Acciani, Timothy D. LeCras, Jocelyn Biagini Myers, Melinda Butsch Kovacic, Ian P. Lewkowich

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)462-471.e14
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number2
DOIs
StatePublished - Feb 1 2017

Keywords

  • Asthma
  • IL-13
  • IL-17A
  • cytokines
  • signal transducer and activator of transcription 6
  • signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Hall, S. L., Baker, T., Lajoie, S., Richgels, P. K., Yang, Y., McAlees, J. W., van Lier, A., Wills-Karp, M., Sivaprasad, U., Acciani, T. H., LeCras, T. D., Myers, J. B., Kovacic, M. B., & Lewkowich, I. P. (2017). IL-17A enhances IL-13 activity by enhancing IL-13–induced signal transducer and activator of transcription 6 activation. Journal of Allergy and Clinical Immunology, 139(2), 462-471.e14. https://doi.org/10.1016/j.jaci.2016.04.037