Epithelial Cell-Derived IL-25, but Not Th17 Cell-Derived IL-17 or IL-17F, Is Crucial for Murine Asthma

  • Maho Suzukawa
    Department of Internal Medicine, Teikyo University School of Medicine , Tokyo 173-8605,
  • Hideaki Morita
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Aya Nambu
    Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639,
  • Ken Arae
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Eri Shimura
    Atopy Research Center, Juntendo University School of Medicine , Tokyo 113-8421,
  • Akiko Shibui
    Department of Medical Genomics, Graduate School of Frontier Sciences, The University of Tokyo , Chiba 278-0022,
  • Sachiko Yamaguchi
    Frontier Research Initiative, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639,
  • Keigo Suzukawa
    Department of Otolaryngology Head and Neck Surgery, The University of Tokyo , Tokyo 113-8655,
  • Wakako Nakanishi
    Department of Otolaryngology Head and Neck Surgery, The University of Tokyo , Tokyo 113-8655,
  • Keisuke Oboki
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Naoki Kajiwara
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Tatsukuni Ohno
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Akina Ishii
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Heinrich Körner
    Menzies Research Institute , Hobart, Tas 7000,
  • Daniel J Cua
    Merck Research Laboratories , Palo Alto, CA 94304
  • Hajime Suto
    Atopy Research Center, Juntendo University School of Medicine , Tokyo 113-8421,
  • Takayuki Yoshimoto
    Intractable Immune System Disease Research Center, Tokyo Medical University , Tokyo 160-8402,
  • Yoichiro Iwakura
    Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639,
  • Tatsuya Yamasoba
    Department of Otolaryngology Head and Neck Surgery, The University of Tokyo , Tokyo 113-8655,
  • Ken Ohta
    Department of Internal Medicine, Teikyo University School of Medicine , Tokyo 173-8605,
  • Katsuko Sudo
    Animal Research Center, Tokyo Medical University , Tokyo 160-8402,
  • Hirohisa Saito
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Ko Okumura
    Atopy Research Center, Juntendo University School of Medicine , Tokyo 113-8421,
  • David H Broide
    Department of Medicine, University of California , San Diego, La Jolla, CA 92037
  • Kenji Matsumoto
    Department of Allergy and Immunology, National Research Institute for Child Health and Development , Tokyo 157-8535,
  • Susumu Nakae
    Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639,

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<jats:title>Abstract</jats:title> <jats:p>IL-17A, IL-17F, and IL-25 are ligands for IL-17RA. In the current study, we demonstrated that IL-25–deficient mice—but not IL-17A–, IL-17F–, IL-17A/F–, IL-23p19–, or retinoic acid-related orphan receptor (ROR)-γt–deficient mice—showed significant suppression of 1) the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, 2) airway hyperresponsiveness to methacholine, and 3) OVA-specific IgG1 and IgE levels in the serum during OVA-induced Th2-type/eosinophilic airway inflammation. The IL-25 deficiency did not affect lung dendritic cell migration or Ag-specific memory–Th2 cell expansion during Ag sensitization. Adoptive transfer of T cells, mast cells, or bone marrow cells from IL-25–deficient mice revealed that induction of Th2-type/eosinophilic airway inflammation was dependent on activation of lung epithelial cells and eosinophils by IL-25 produced by airway structural cells such as epithelial cells but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells. Therefore, airway structural cell-derived IL-25—rather than Th17 cell-derived IL-17A and IL-17F—is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase of Th2-type/eosinophilic airway inflammation. It is not required for Ag-specific Th2 cell differentiation in the sensitization phase.</jats:p>

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