Interleukin-1β mediates virus-induced M2 muscarinic receptor dysfunction and airway hyperreactivity

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15 Scopus citations

Abstract

Respiratory viral infections are associated with the majority of asthma attacks. Inhibitory M2 receptors on parasympathetic nerves, which normally limit acetylcholine (ACh) release, are dysfunctional after respiratory viral infection. Because IL-1β is up-regulated during respiratory viral infections, we investigated whether IL-1β mediates M2 receptor dysfunction during parainfluenza virus infection. Virus-infected guinea pigs were pretreated with the IL-1β antagonist anakinra. In the absence of anakinra, viral infection increased bronchoconstriction in response to vagal stimulation but not to intravenous ACh, and neuronal M2 muscarinic receptors were dysfunctional. Pretreatment with anakinra prevented virus-induced increased bronchoconstriction and M2 receptor dysfunction. Anakinra did not change smooth muscle M3 muscarinic receptor response to ACh, lung viral loads, or blood and bronchoalveolar lavage leukocyte populations. Respiratory virus infection decreased M2 receptor mRNA expression in parasympathetic ganglia extracted from infected animals, and this was prevented by blocking IL-1β or TNF-α. Treatment of SK-N-SH neuroblastoma cells or primary cultures of guinea pig parasympathetic neurons with IL-1β directly decreasedM2 receptor mRNA, and this was not synergistic with TNF-αtreatment. Treating guinea pig trachea segment with TNF-αor IL-1β in vitro increased tracheal contractions in response to activation of airway nerves by electrical field stimulation. Blocking IL-1β during TNF-α treatment prevented this hyperresponsiveness. These data show that virus-induced hyperreactivity and M2 dysfunction involves IL-1β and TNF-α, likely in sequence with TNF-αcausing production of IL-1β.

Original languageEnglish (US)
Pages (from-to)494-501
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume51
Issue number4
DOIs
StatePublished - Oct 1 2014

Keywords

  • Asthma
  • IL-1β
  • Parainfluenza virus
  • Parasympathetic nerves
  • TNF-α

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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