1. IFN-γ elevates airway hyper-responsiveness via up-regulation of neurokinin A/neurokinin-2 receptor signaling in a severe asthma model.
- Author
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Kobayashi M, Ashino S, Shiohama Y, Wakita D, Kitamura H, and Nishimura T
- Subjects
- Animals, Asthma chemically induced, Asthma genetics, Asthma physiopathology, Bronchial Hyperreactivity, Calcium Signaling genetics, Cells, Cultured, Disease Models, Animal, Disease Progression, Gene Expression Regulation genetics, Gene Expression Regulation immunology, Humans, Interferon-gamma immunology, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Myocytes, Smooth Muscle immunology, Myocytes, Smooth Muscle pathology, Neuroimmunomodulation, Neurokinin A genetics, Neurokinin A immunology, Receptors, Neurokinin-2 genetics, Receptors, Neurokinin-2 immunology, Respiratory System pathology, STAT1 Transcription Factor genetics, Asthma immunology, Interferon-gamma metabolism, Myocytes, Smooth Muscle metabolism, Neurokinin A metabolism, Receptors, Neurokinin-2 metabolism
- 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., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
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