title: EGCG blocks TGFβ1-induced CCN2 by suppressing JNK and p38 in buccal fibroblasts.
abstract: OBJECTIVE
  Transforming growth factor β (TGFβ) has been suggested as the main trigger for the increased collagen production and decreased matrix degradation pathways in oral submucous fibrosis (OSF). Connective tissue growth factor (CTGF/CCN2) and cyclooxygenase-2 (COX-2) were found to overexpress in OSF. The aim of this study was to investigate the molecular mechanism underlying the TGFβ-induced CCN2 expressions in human buccal mucosal fibroblasts (BMFs) to identify the potential targets for drug intervention or chemoprevention of OSF.
  
  
  METHODS
  TGFβ-induced CCN2 expression and its signaling pathways were assessed by Western blot analyses in BMFs.
  
  
  RESULTS
  TGFβ1 stimulated CCN2 synthesis in BMFs. Pretreatment with c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, and activin receptor-like kinase 5 (ALK5) inhibitor SB431542 significantly reduced TGFβ1-induced CCN2 synthesis. Epigallocatechin-3-gallate (EGCG) completely blocked TGFβ1-induced CCN2 synthesis by inhibiting the phosphorylation of JNK and p38 MAPK. Prostaglandin E(2) (PGE(2)) inhibited the TGFβ1-induced CCN2 synthesis in human fetal lung fibroblasts IMR90 but not in BMFs.
  
  
  CONCLUSIONS
  The TGFβ1-induced CCN2 synthesis in BMFs could be mediated by the ALK5, JNK, and p38 MAPK pathways. EGCG blocks TGFβ1-induced CCN2 by suppressing JNK and p38 in BMFs.
  
  
  CONCLUSIONS
  The exceptional signal transduction pathways of TGFβ1-induced CCN2 production in BMFs contribute to the resistance of PGE(2) downregulation of CCN2 expression; therefore, the CTGF/CCN2 levels are maintained in the OSF tissues in the presence of COX-2. EGCG may serve as a useful agent in controlling OSF.
authors.affiliation: School of Dentistry, College of Medicine and Department of Dentistry, National Taiwan University Hospital, National Taiwan University, No 1, Chang-Te Street, Taipei 10048, Taiwan.
authors.forename: Jenny Zwei-Chieng
authors.initials: JZ
authors.lastname: Chang
authors.forename: Wan-Hsien
authors.initials: WH
authors.lastname: Yang
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Deng
authors.forename: Hsin-Ming
authors.initials: HM
authors.lastname: Chen
authors.forename: Mark Yen-Ping
authors.initials: MY
authors.lastname: Kuo
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects*; D009914:Oral Submucous Fibrosis / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000873:Anthracenes; D001549:Benzamides; C526317:CCN2 protein, human; D004149:Dioxoles; D005419:Flavonoids; D007093:Imidazoles; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C432165:pyrazolanthrone; D002392:Catechin; C045651:epigallocatechin gallate; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; D048670:MAP Kinase Kinase 4; D015232:Dinoprostone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one