title: IL-17A enhances IL-13 activity by enhancing IL-13-induced signal transducer and activator of transcription 6 activation.
abstract: 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.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Hall
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Theresa
authors.initials: T
authors.lastname: Baker
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md.
authors.forename: Stephane
authors.initials: S
authors.lastname: Lajoie
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Phoebe K
authors.initials: PK
authors.lastname: Richgels
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jaclyn W
authors.initials: JW
authors.lastname: McAlees
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Adelaide
authors.initials: A
authors.lastname: van Lier
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md.
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Umasundari
authors.initials: U
authors.lastname: Sivaprasad
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Acciani
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: LeCras
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jocelyn Biagini
authors.initials: JB
authors.lastname: Myers
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Melinda Butsch
authors.initials: MB
authors.lastname: Kovacic
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Ian.Lewkowich@cchmc.org.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Lewkowich
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; C491673:Il17ra protein, mouse; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D050800:STAT6 Transcription Factor
keywords: Asthma; IL-13; IL-17A; cytokines; signal transducer and activator of transcription 6; signal transduction