Regulatory effects of IL-15 on allergen-induced airway obstruction

Background: Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis. Objective: 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. Methods: 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. Results: 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-gamma- and IL-10-producing regulatory CD4(+) CD25(+) 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. Conclusion: We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.