1 Department of Molecular Microbiology and Immunology, and.
Am J Respir Cell Mol Biol. 2014 Oct;51(4):494-501. doi: 10.1165/rcmb.2014-0009OC.
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 decreased M2 receptor mRNA, and this was not synergistic with TNF-α treatment. Treating guinea pig trachea segment with TNF-α or 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-α causing production of IL-1β.
呼吸道病毒感染与大多数哮喘发作有关。副交感神经上的抑制性 M2 受体在呼吸道病毒感染后功能失调，正常情况下它限制乙酰胆碱（ACh）的释放。由于白细胞介素-1β（IL-1β）在呼吸道病毒感染期间上调，我们研究了 IL-1β 是否在副流感病毒感染期间介导 M2 受体功能障碍。病毒感染的豚鼠用 IL-1β 拮抗剂 anakinra 预处理。在没有 anakinra 的情况下，病毒感染增加了对迷走神经刺激的支气管收缩反应，但对静脉内 ACh 没有影响，并且神经元 M2 毒蕈碱受体功能失调。用 anakinra 预处理可预防病毒引起的支气管收缩增加和 M2 受体功能障碍。anakinra 不改变平滑肌 M3 毒蕈碱受体对 ACh 的反应、肺病毒载量或血液和支气管肺泡灌洗液白细胞群。呼吸道病毒感染降低了从感染动物提取的副交感神经节中 M2 受体 mRNA 的表达，而阻断 IL-1β 或 TNF-α 可预防这种降低。用 IL-1β 直接处理 SK-N-SH 神经母细胞瘤细胞或豚鼠副交感神经元的原代培养物可降低 M2 受体 mRNA 的表达，且这种作用与 TNF-α 治疗没有协同作用。在体外，用 TNF-α 或 IL-1β 处理豚鼠气管段可增加对气道神经电刺激激活的气管收缩。在 TNF-α 治疗期间阻断 IL-1β 可防止这种高反应性。这些数据表明，病毒诱导的高反应性和 M2 功能障碍涉及 IL-1β 和 TNF-α，可能是 TNF-α 引起 IL-1β 的产生。
