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Published ahead of print on August 23, 2007, doi:10.1165/rcmb.2007-0173OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 2, February 2008, 153-160

A more recent version of this article appeared on February 1, 2008
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Submitted on May 16, 2007
Revised on August 23, 2007

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

Sima Allahverdian1, Norihiro Harada2, Gurpreet K Singhera1, Darryl A Knight1, and Delbert R Dorscheid1*

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, 2 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; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: Ddorscheid{at}mrl.ubc.ca.

Inappropriate repair following 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-dependant manner coordinate with repair. Neutralizing of IL-13 secreted from injured epithelial cells by shIL-13R{alpha}2.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, EGF and 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.




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