title: Interleukin-17A directly acts on bronchial smooth muscle cells and augments the contractility.
abstract: BACKGROUND
  Although interleukin-17 (IL-17) contributes to the induction of airway hyperresponsiveness in asthma, its effect on bronchial smooth muscle (BSM) remains largely unknown. Evidence support an involvement of RhoA/Rho-kinase in BSM contraction, and the pathway has now been proposed as a novel target for asthma therapy. To clarify the role of IL-17 on the development of BSM hyperresponsiveness, effects of IL-17A on BSM contractility and RhoA expression were investigated.
  
  
  METHODS
  Male BALB/c mice and cultured human BSM cells (hBSMCs) were used.
  
  
  RESULTS
  In the murine model of allergic asthma, BSM hyperresponsiveness with an IL-17A up-regulation in bronchoalveolar lavage fluids were observed. RT-PCR analyses revealed the expression of receptors for IL-17A in mouse BSMs and hBSMCs. In the hBSMCs, incubation with IL-17A caused an up-regulation of RhoA protein. Western blot analyses also revealed phosphorylations of JNKs/ERKs and a down-regulation of IκB-α in the IL-17A-treated hBSMCs, indicating that IL-17A could act on BSM cells directly. However, IL-17A did not activate STAT6, which is also known as a signaling molecule that causes an up-regulation of RhoA when activated by IL-13. On the other hand, IL-17A caused a down-regulation of miR-133a-3p, a microRNA that negatively regulates RhoA translation. In the naive mice, in vivo IL-17A treatment to the airways by intranasal instillation induced a BSM hyperresponsiveness with RhoA protein up-regulation.
  
  
  CONCLUSIONS
  These findings indicate that IL-17 directly acts on BSM cells and up-regulates RhoA protein probably via a down-regulation of miR-133a-3p, resulting in an induction of the BSM hyperresponsiveness.
authors.affiliation: Department of Biology, School of Pharmacy, Hoshi University, Tokyo, Japan. Electronic address: chiba@hoshi.ac.jp.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Chiba
authors.affiliation: Department of Biology, School of Pharmacy, Hoshi University, Tokyo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Tanoue
authors.affiliation: Department of Biology, School of Pharmacy, Hoshi University, Tokyo, Japan.
authors.forename: Rena
authors.initials: R
authors.lastname: Suto
authors.affiliation: Department of Biology, School of Pharmacy, Hoshi University, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Suto
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Hanazaki
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katayama
authors.affiliation: Department of Analytical Pathophysiology, School of Pharmacy, Hoshi University, Tokyo, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
mesh_terms: D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Airway hyperresponsiveness; Asthma; Interleukin-17; RhoA; miRNA