Rynko_2014_Am.J.Respir.Cell.Mol.Biol_51_494

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-1beta is up-regulated during respiratory viral infections, we investigated whether IL-1beta mediates M2 receptor dysfunction during parainfluenza virus infection. Virus-infected guinea pigs were pretreated with the IL-1beta 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-1beta or TNF-alpha. Treatment of SK-N-SH neuroblastoma cells or primary cultures of guinea pig parasympathetic neurons with IL-1beta directly decreased M2 receptor mRNA, and this was not synergistic with TNF-alpha treatment. Treating guinea pig trachea segment with TNF-alpha or IL-1beta in vitro increased tracheal contractions in response to activation of airway nerves by electrical field stimulation. Blocking IL-1beta during TNF-alpha treatment prevented this hyperresponsiveness. These data show that virus-induced hyperreactivity and M2 dysfunction involves IL-1beta and TNF-alpha, likely in sequence with TNF-alpha causing production of IL-1beta.