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

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.