title: Epigallocatechin-3-gallate inhibits transforming-growth-factor-β1-induced collagen synthesis by suppressing early growth response-1 in human buccal mucosal fibroblasts.
abstract: OBJECTIVE
  Transforming growth factor (TGF)-β is a key regulator in the pathogenesis of oral submucous fibrosis (OSF). Early growth response (Egr)-1 is essential for fibrotic responses to TGF-β. Because TGF-β signaling is cell-type- and context-dependent, we investigated the signaling involved in TGF-β-induced Egr-1 in primary human buccal mucosal fibroblasts (BMFs).
  
  
  METHODS
  TGF-β-induced Egr-1 and its signaling were assessed by western blotting in BMFs. Egr-1 small interfering RNA was used to define the role of Egr-1 on TGF-β-induced mRNAs of the α1- and α2-chains of type I collagen (COL1A1 and COL1A2) and acid-soluble collagen production (via Sircol collagen assay). The effects of epigallocatechin-3-gallate (EGCG) on TGF-β-induced Egr-1 protein and acid-soluble collagen were also evaluated.
  
  
  RESULTS
  TGF-β1 stimulated Egr-1 production in BMFs. Pretreatment with PD98059, SP600125, SB431542, and SIS3, but not SB203580, significantly reduced TGF-β1-induced Egr-1 protein expression. Genetic targeting of Egr-1 completely inhibited TGF-β1-induced type I collagen mRNAs and collagen protein expression. EGCG fully inhibited TGF-β1-induced Egr-1 and TGF-β1-stimulated production of acid-soluble collagens.
  
  
  CONCLUSIONS
  We conclude that activin receptor-like kinase (ALK)5, Smad3, extracellular signal-regulated kinase, and c-Jun N-terminal kinase are involved in the TGF-β1-induced Egr-1 protein production in BMFs. Egr-1 mediates TGF-β1-induced COL1A1 and COL1A2 mRNA expression and acid-soluble collagen production in BMFs. EGCG can block TGF-β1-induced collagen production by attenuating Egr-1 expression in BMFs. Egr-1 is a key mediator in TGF-β1-induced pathogenesis of OSF. EGCG may be useful in the prevention or treatment of OSF.
authors.affiliation: Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsin-Ming
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsiang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: jennyzc@ms3.hinet.net.
authors.forename: Jenny Zwei-Chieng
authors.initials: JZ
authors.lastname: Chang
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D004149:Dioxoles / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D009061:Mouth Mucosa / Q000166:cytology; D009914:Oral Submucous Fibrosis / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000873:Anthracenes; D001549:Benzamides; D024042:Collagen Type I; D004149:Dioxoles; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005419:Flavonoids; D053773:Transforming Growth Factor beta1; C432165:pyrazolanthrone; D002392:Catechin; C045651:epigallocatechin gallate; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: early growth response-1; epigallocatechin-3-gallate; fibroblast; oral submucous fibrosis; transforming growth factor β