Interleukin-1β Mediates Virus-Induced M2 Muscarinic Receptor Dysfunction and Airway Hyperreactivity

Respiratory viral infections are associated with the majority of asthma attacks. Inhibitory M-2 receptors on parasympathetic nerves, which normally limit acetylcholine (ACh) release, are dysfunctional after respiratory viral infection. Because IL-1 beta is up-regulated during respiratory viral infections, we investigated whether IL-1 beta mediates M-2 receptor dysfunction during parainfluenza virus infection. Virus-infected guinea pigs were pretreated with the IL-1 beta antagonist anakinra. In the absence of anakinra, viral infection increased bronchoconstriction in response to vagal stimulation but not to intravenous ACh, and neuronal M-2 muscarinic receptors were dysfunctional. Pretreatment with anakinra prevented virus-induced increased bronchoconstriction and M-2 receptor dysfunction. Anakinra did not change smooth muscle M-3 muscarinic receptor response to ACh, lung viral loads, or blood and bronchoalveolar lavage leukocyte populations. Respiratory virus infection decreased M-2 receptor mRNA expression in parasympathetic ganglia extracted from infected animals, and this was prevented by blocking IL-1 beta or TNF-alpha. Treatment of SK-N-SH neuroblastoma cells or primary cultures of guinea pig parasympathetic neurons with IL-1 beta directly decreased M2 receptor mRNA, and this was not synergistic with TNF-alpha treatment. Treating guinea pig trachea segment with TNF-alpha or IL-1 beta in vitro increased tracheal contractions in response to activation of airway nerves by electrical field stimulation. Blocking IL-1 beta during TNF-alpha treatment prevented this hyperresponsiveness. These data show that virus-induced hyperreactivity and M-2 dysfunction involves IL-1 beta and TNF-alpha, likely in sequence with TNF-alpha causing production of IL-1 beta.