Original Article

Interleukin-17A is involved in development of spontaneous pulmonary emphysema caused by Toll-like receptor 4 mutation

Authors: Qing-qing Wang, Hong-zhen Yang, Han-zhi Liu, Su Mi, Xiao-wei Zhang, Hui-min Yan, Yong-gang Ma, Xiao-xing Wang, Zhuo-wei Hu
DOI: 10.1038/aps.2011.67

Abstract

Aim: To explore the pathogenic role of Th17 cells and interleukin-17A (IL-17A)-associated signaling pathways in spontaneous pulmonary emphysema induced by a Toll-like receptor 4 mutant (TLR4mut).
Methods: Lungs were obtained from wild-type (WT) or TLR4mut mice that were treated with or without recombinant mouse IL-17A (1 μg·kg−1·d−1, ip) from the age of 3 weeks to 3 months. Pulmonary emphysema was determined using histology, immunochemistry, and biochemical analysis. T cell polarization was determined with flow cytometry, the levels of cytokines were measured using ELISA, and the levels of IL-17A-associated signaling molecules were detected using Western blot.
Results: Compared to WT mice, 3 month-old TLR4mut mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%±1.13 % vs. 5.26%±1.39%), and significantly reduced expression levels of IL-17A (3.66±0.99 pg/μg vs. 10.67±1.65 pg/μg), IL-23 (12.43±1.28 pg/μg vs. 28.71±2.57 pg/μg) and IL-6 (51.82±5.45 pg/μg vs. 92.73±10.91 pg/μg) in bronchoalveolar lavage fluid. In addition, p38 MAPK phosphorylation and AP-1 expression were decreased to 27%±9% and 51%±8%, respectively, of that in WT mice. Treatment of TLR4mut mice with IL-17A increased the infiltration of Th17 cells into lungs and expression levels of IL-17A, IL-6, and IL-23 in bronchoalveolar lavage fluid, attenuated MDA and apoptosis, and improved emphysema accompanied with increased phosphorylation of p38 MAPK and expression of AP-1.
Conclusion: Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4mut-induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema.
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