title: IFN-γ elevates airway hyper-responsiveness via up-regulation of neurokinin A/neurokinin-2 receptor signaling in a severe asthma model.
abstract: The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-γ. The administration of IFN-γ instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1(-/-)  mice after stimulation with IFN-γ. In addition, methacholine-mediated Ca(2+)  influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-γ-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-γ directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma.
authors: Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors: Minoru
authors: M
authors: Kobayashi
authors: Shigeru
authors: S
authors: Ashino
authors: Yasuo
authors: Y
authors: Shiohama
authors: Daiko
authors: D
authors: Wakita
authors: Hidemitsu
authors: H
authors: Kitamura
authors: Takashi
authors: T
authors: Nishimura
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity; D020013:Calcium Signaling / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015213:Neuroimmunomodulation; D015288:Neurokinin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012137:Respiratory System / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000235:genetics
chemical_list: D018041:Receptors, Neurokinin-2; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D015288:Neurokinin A