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Secretion of IL-13 by Airway Epithelial Cells Enhances Epithelial Repair via HB-EGF

¹ The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Faculty of Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; and ² Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Delbert R. Dorscheid, M.D., Ph.D., The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 166, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: ddorscheid{at}mrl.ubc.ca

Inappropriate repair after injury to the epithelium generates persistent activation, which may contribute to airway remodeling. In the present study we hypothesized that IL-13 is a normal mediator of airway epithelial repair. Mechanical injury of confluent airway epithelial cell (AEC) monolayers induced expression and release of IL-13 in a time-dependent manner coordinate with repair. Neutralizing of IL-13 secreted from injured epithelial cells by shIL-13R2.FC significantly reduced epithelial repair. Moreover, exogenous IL-13 enhanced epithelial repair and induced epidermal growth factor receptor (EGFR) phosphorylation. We examined secretion of two EGFR ligands, epidermal growth factor (EGF) and heparin-binding EGF (HB-EGF), after mechanical injury. Our data showed a sequential release of the EGF and HB-EGF by AEC after injury. Interestingly, we found that IL-13 induces HB-EGF, but not EGF, synthesis and release from AEC. IL-13–induced EGFR phosphorylation and the IL-13–reparative effect on AEC are mediated via HB-EGF. Finally, we demonstrated that inhibition of EGFR tyrosine kinase activity by tyrphostin AG1478 increases IL-13 release after injury, suggesting negative feedback between EGFR and IL-13 during repair. Our data, for the first time, showed that IL-13 plays an important role in epithelial repair, and that its effect is mediated through the autocrine release of HB-EGF and activation of EGFR. Dysregulation of EGFR phosphorylation may contribute to a persistent repair phenotype and chronically increased IL-13 release, and in turn result in airway remodeling.

Key Words: asthma • bronchial epithelium • epithelial repair • epidermal growth factor • interleukin-13

CLINICAL RELEVANCE The mechanisms for airway remodeling in asthma remain unknown. Elevated IL-13 and persistent airway epithelial damage are demonstrated in asthma. The presentation of IL-13–enhanced repair suggests that a defect in the process of repair may contribute to remodeling.