Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, La.
Section of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
J Allergy Clin Immunol. 2018 Mar;141(3):906-917.e6. doi: 10.1016/j.jaci.2017.05.025. Epub 2017 Jun 9.
Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis.
We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine.
Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA.
We made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-γ- and IL-10-producing regulatory CD4CD25 forkhead box p3 (Foxp3) T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model.
We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.
气道阻塞是哮喘的一种生理特征，IL-15 可能在哮喘发病机制中起重要作用。
我们检验了这样一个假设，即调节 IL-15 对于维持变应原诱导的气道高反应性（AHR）、气道阻力和对乙酰甲胆碱的顺应性至关重要。
在变应原诱导的哮喘小鼠模型中，检测 IL-15 基因缺失小鼠和 IL-15 过表达小鼠的气道炎症、AHR、阻力和顺应性。通过抗主要碱性蛋白免疫染色评估嗜酸性粒细胞数量，通过过碘酸-希夫染色评估杯状细胞增生，通过定量 PCR 和 ELISA 评估细胞因子和趋化因子水平。
我们有了一个新的发现，即 IL-15 缺乏会促进未致敏小鼠的基础气道阻力。此外，肺内 rIL-15 的传递可下调促炎细胞因子的表达，并改善变应原诱导的 AHR、气道阻力和顺应性。这些观察结果在强力霉素诱导的 CC10-IL-15 双转基因小鼠中得到进一步验证。强力霉素暴露、曲霉菌提取物刺激的 CC10-IL-15 双转基因小鼠表现出显著降低的促炎细胞因子（IL-4、IL-5 和 IL-13）水平和杯状细胞增生减少。与未暴露于强力霉素的 CC10-IL-15 双转基因小鼠相比，变应原刺激下暴露于强力霉素的 CC10-IL-15 双转基因小鼠的气道阻塞，包括 AHR 和气道阻力，均有所减轻。从机制上讲，我们观察到 IL-15 介导的气道阻塞保护与诱导 IFN-γ 和 IL-10 产生的调节性 CD4+CD25+叉头框 P3（Foxp3）T 细胞有关。此外，我们发现一种人 IL-15 激动剂（ALT-803）可改善实验性哮喘模型中的气道阻力和顺应性。
我们报告了一个新发现，即 IL-15 对环境变应原引起的气道阻塞具有强大的抑制作用。
