title: Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF.
abstract: 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-13Ralpha2.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.
authors: James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 166, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada.
authors: Sima
authors: S
authors: Allahverdian
authors: Norihiro
authors: N
authors: Harada
authors: Gurpreet K
authors: GK
authors: Singhera
authors: Darryl A
authors: DA
authors: Knight
authors: Delbert R
authors: DR
authors: Dorscheid
mesh_terms: D001483:Base Sequence; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002461:Cell Line, Transformed; D016895:Culture Media, Serum-Free; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism*; D008024:Ligands; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016895:Culture Media, Serum-Free; D017931:DNA Primers; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D008024:Ligands; D066246:ErbB Receptors
references: Am J Physiol Lung Cell Mol Physiol. 2002 Jul;283(1):L67-75
references: 12060562
references: Am J Respir Cell Mol Biol. 2001 Dec;25(6):739-43
references: 11726400
references: Respirology. 2003 Dec;8(4):432-46
references: 14708552
references: Respir Med. 2004 Sep;98(9):821-5
references: 15338792
references: J Allergy Clin Immunol. 2004 Sep;114(3):657-63
references: 15356573
references: Lung. 1993;171(6):335-44
references: 8295428
references: J Biol Chem. 1995 Jan 20;270(3):1015-9
references: 7836353
references: Am J Physiol. 1995 Mar;268(3 Pt 1):L347-60
references: 7900815
references: J Immunol. 1997 May 15;158(10):5050-7
references: 9144526
references: J Allergy Clin Immunol. 1997 May;99(5):657-65
references: 9155833
references: J Clin Invest. 1997 Sep 1;100(5):1271-81
references: 9276746
references: Science. 1998 Dec 18;282(5397):2258-61
references: 9856949
references: J Clin Invest. 1999 Mar;103(6):779-88
references: 10079098
references: Am J Respir Cell Mol Biol. 1999 May;20(5):914-23
references: 10226061
references: Am J Respir Cell Mol Biol. 2005 May;32(5):373-80
references: 15705969
references: Nat Med. 2006 Jan;12(1):99-106
references: 16327802
references: J Clin Invest. 2006 Feb;116(2):309-21
references: 16453019
references: Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L828-36
references: 16751224
references: J Allergy Clin Immunol. 2006 Oct;118(4):858-65
references: 17030238
references: Am J Respir Cell Mol Biol. 2002 Jul;27(1):85-90
references: 12091250
references: Am J Physiol Lung Cell Mol Physiol. 2001 Jan;280(1):L134-40
references: 11133503
references: Invest Ophthalmol Vis Sci. 2000 May;41(6):1346-55
references: 10798649
references: FASEB J. 2000 Jul;14(10):1362-74
references: 10877829
references: Am J Respir Cell Mol Biol. 2001 Feb;24(2):123-31
references: 11159045
references: Exp Eye Res. 2001 May;72(5):511-7
references: 11311043
references: Endocr Relat Cancer. 2001 Mar;8(1):11-31
references: 11350724
references: Am J Physiol Lung Cell Mol Physiol. 2001 Oct;281(4):L982-92
references: 11557602
references: Am J Physiol Cell Physiol. 2003 Nov;285(5):C1028-35
references: 12826601