Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts.
Elastase degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. In addition to elastolytic activities, elastases release growth factors from extracellular matrices and interstitial cell surfaces that can regulate elastogenesis and other cellular responses. In the present study, we demonstrate that brief treatment of matrix-laden rat pulmonary fibroblast cultures with pancreatic elastase results in the release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) concomitant with a decrease in HB-EGF binding to both heparan sulfate proteoglycan and receptor sites on the cells. In undigested, matrix-laden fibroblasts, HB-EGF significantly downregulates elastin mRNA via activation of epidermal growth factor receptor. Results from nuclear run-on analyses show that HB-EGF downregulates elastin mRNA via transcriptional suppression. HBEGF treatment stimulates MAP or ERK kinase (MEK)-dependent ERK1/2 phosphorylation and leads to nuclear accumulation of Fra-1. Blocking ERK1/2 activation by MEK1/2 inhibitors (PD-98059 or U-0126) diminishes HB-EGF-induced Fra-1 accumulation and subsequent downregulation of elastin mRNA. Coaddition of two elastase-released growth factors, HB-EGF and FGF-2, results in an additive inhibitory effect on elastin mRNA levels. Furthermore, HB-EGF addition to pulmonary fibroblasts increases FGF-2 mRNA and protein levels. These data suggest that HB-EGF and FGF-2 act in concert to regulate the synthesis of elastin in injury/repair situations.
Liu
Jianghuai
J
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Rich
Celeste B
CB
Buczek-Thomas
Jo Ann
JA
Nugent
Matthew A
MA
Panchenko
Mikhail P
MP
Foster
Judith Ann
JA
D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002478:Cells, Cultured; D004549:Elastin / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000493:pharmacokinetics / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010196:Pancreatic Elastase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D005419:Flavonoids; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D006493:Heparin; D004549:Elastin; D010196:Pancreatic Elastase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one