The overexpression of heparin-binding epidermal growth factor is responsible for Th17-induced airway remodeling in an experimental asthma model.
Th17 cells that produce IL-17 have been found to participate in the development of allergy-triggered asthma. However, whether they play a causative role in the pathogenesis of airway remodeling in chronic asthma remains unclear. In this study, we investigated the role of Th17 cells in airway remodeling and the possible involvement of epidermal growth factor (EGF) receptor signals downstream of Th17. We established a C57BL/6 mouse model of prolonged allergen challenge that exhibits many characteristics of airway remodeling. Prolonged allergen challenge induced a progressive increase in the number of airway-infiltrating Th17 cells, and Th17 counts positively correlated with the severity of airway remodeling. Increases in mucus production, airway smooth muscle (ASM) mass, peribronchial collagen deposition, and airway heparin-binding EGF (HB-EGF) expression have been observed in sensitized mice following prolonged allergen exposure or adoptive Th17 transfer; remarkably, these effects can be abrogated by treatment with anti-IL-17 mAb. Both the EFGR inhibitor AG1478 and an anti-HB-EGF mAb ameliorated all of these effects, except for peribronchial collagen deposition in the presence of high levels of IL-17. In vitro, Th17 cells enhanced the airway epithelial expression of HB-EGF in a coculture of the two cells. The conditioned medium obtained from this coculture system effectively promoted ASM proliferation; this response was dramatically abolished by anti-HB-EGF mAb but not Abs against other EGF receptor ligands or IL-17. These observations demonstrated that overexpression of airway HB-EGF induced by IL-17 secreted from redundant expanding Th17 cells might contribute to excessive mucus expression and ASM proliferation in chronic asthma.
Wang
Qing
Q
Department of Respiratory Diseases, First Affiliated Hospital of College of Medicine, Hangzhou, Zhejiang, People's Republic of China.
Li
Hequan
H
Yao
Yinan
Y
Xia
Dajing
D
Zhou
Jianying
J
D019264:Adoptive Transfer; D056151:Airway Remodeling / Q000187:drug effects / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000276:immunology*; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011799:Quinazolines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D020032:Tyrphostins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D004791:Enzyme Inhibitors; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D010047:Ovalbumin; D066246:ErbB Receptors