title: Interleukin-17A is involved in development of spontaneous pulmonary emphysema caused by Toll-like receptor 4 mutation.
abstract: OBJECTIVE
  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 (TLR4(mut)).
  
  
  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 TLR4(mut) mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%±1.13 % νs 5.26%±1.39%), and significantly reduced expression levels of IL-17A (3.66±0.99 pg/μg νs 10.67±1.65 pg/μg), IL-23 (12.43±1.28 pg/μg νs 28.71±2.57 pg/μg) and IL-6 (51.82±5.45 pg/μg νs 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 TLR4(mut) 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.
  
  
  CONCLUSIONS
  Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4(mut)-induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema.
authors.affiliation: Molecular Immunology and Pharmacology Laboratory, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Qing-qing
authors.initials: QQ
authors.lastname: Wang
authors.forename: Hong-zhen
authors.initials: HZ
authors.lastname: Yang
authors.forename: Han-zhi
authors.initials: HZ
authors.lastname: Liu
authors.forename: Su
authors.initials: S
authors.lastname: Mi
authors.forename: Xiao-wei
authors.initials: XW
authors.lastname: Zhang
authors.forename: Hui-min
authors.initials: HM
authors.lastname: Yan
authors.forename: Yong-gang
authors.initials: YG
authors.lastname: Ma
authors.forename: Xiao-xing
authors.initials: XX
authors.lastname: Wang
authors.forename: Zhuo-wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000818:Animals; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation / Q000235:genetics; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4