title: Wound-induced TGF-β1 and TGF-β2 enhance airway epithelial repair via HB-EGF and TGF-α.
abstract: The abundance of transforming growth factor-beta (TGF-β) in normal airway epithelium suggests its participation in physiological processes to maintain airway homeostasis. The current study was designed to address the hypothesis that TGF-β1 and TGF-β2 might contribute to normal reparative response of airway epithelial cells (AECs). Treatments with exogenous TGF-β1 or TGF-β2 significantly enhanced wound repair of confluent AEC monolayers. Mechanical injury of AEC monolayers induced production of both TGF-β1 and TGF-β2. Wound repair of AECs was significantly reduced by a specific inhibitor of TGF-β type I receptor kinase activity. We investigated whether the TGF-β-enhanced repair required epidermal growth factor receptor (EGFR) transactivation and secretion of EGFR ligands. Both TGF-β1 and TGF-β2 enhanced EGFR phosphorylation and induced production of heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-α) in AECs. Moreover, treatment with a broad-spectrum metalloproteinase inhibitor or anti-HB-EGF and anti-TGF-α antibodies inhibited the wound repair and the EGFR phosphorylation by TGF-β1 and TGF-β2, indicating that the TGF-β1 and TGF-β2 effects on wound repair required the release of HB-EGF and TGF-α. Our data, for the first time, have shown that both TGF-β1 and TGF-β2 play a stimulatory role in airway epithelial repair through EGFR phosphorylation following autocrine production of HB-EGF and TGF-α. These findings highlight an important collaborative mechanism between TGF-β and EGFR in maintaining airway epithelial homeostasis.
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ito
authors.forename: Norihiro
authors.initials: N
authors.lastname: Harada
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagashima
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Makino
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Usui
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Delbert R
authors.initials: DR
authors.lastname: Dorscheid
authors.forename: Ryo
authors.initials: R
authors.lastname: Atsuta
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D010766:Phosphorylation; D012038:Regeneration; D020545:Respiratory Mucosa / Q000187:drug effects / Q000293:injuries* / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C512478:EGFR protein, human; D066246:ErbB Receptors