1 Inflammation Research, and.
2 Genome Analysis Unit, Amgen Inc., Seattle, Washington.
Am J Respir Cell Mol Biol. 2015 Dec;53(6):810-21. doi: 10.1165/rcmb.2015-0038OC.
Asthma is a heterogeneous disease characterized by airway inflammation and hyperreactivity. IL-17 receptor A (IL-17RA) is a shared receptor subunit required for activity of IL-17 family cytokines, including IL-17A and IL-25. IL-17A and IL-25 induce different proinflammatory responses, and concentrations are elevated in subjects with asthma. However, the individual contributions of IL-17A and IL-25 to disease pathogenesis are unclear. We explored proinflammatory activities of the IL-17 pathway in models of pulmonary inflammation and assessed its effects on contractility of human bronchial airway smooth muscle. In two mouse models, IL-17RA, IL-17RB, or IL-25 blockade reduced airway inflammation and airway hyperreactivity. Individually, IL-17A and IL-25 enhanced contractility of human bronchial smooth muscle induced by methacholine or carbachol. IL-17A had more pronounced effects on methacholine-induced contractility in bronchial rings from donors with asthma compared with donors without asthma. Blocking the IL-17 pathway via IL-17RA may be a useful therapy for some patients with asthma by reducing pulmonary inflammation and airway hyperreactivity.
哮喘是一种异质性疾病，其特征为气道炎症和高反应性。白细胞介素 17 受体 A（IL-17RA）是白细胞介素 17 家族细胞因子（包括白细胞介素 17A 和白细胞介素 25）活性所必需的共同受体亚单位。白细胞介素 17A 和白细胞介素 25 诱导不同的促炎反应，并且在哮喘患者中的浓度升高。然而，IL-17A 和白细胞介素 25 对疾病发病机制的个体贡献尚不清楚。我们在肺部炎症模型中研究了白细胞介素 17 通路的促炎活性，并评估了其对人支气管气道平滑肌收缩性的影响。在两种小鼠模型中，IL-17RA、IL-17RB 或 IL-25 阻断减少了气道炎症和气道高反应性。单独地，白细胞介素 17A 和白细胞介素 25 增强了由乙酰甲胆碱或卡巴胆碱诱导的人支气管平滑肌收缩性。与没有哮喘的供体相比，哮喘供体支气管环中白细胞介素 17A 对乙酰甲胆碱诱导的收缩性的影响更为显著。通过 IL-17RA 阻断白细胞介素 17 通路可能是一种有用的哮喘治疗方法，通过减少肺部炎症和气道高反应性。
