Dexamethasone inhibits basic fibroblast growth factor-stimulated gastric epithelial cell proliferation.
Basic fibroblast growth factor (bFGF) is essential for gastric ulcer healing, whereas glucocorticoids delay gastric ulcer healing. We found that dexamethasone inhibited bFGF-stimulated rat gastric epithelial RGM-1 cells proliferation and attempted to elucidate the possible mechanistic pathway. Flowcytometry was used to determine cell proliferation. Western blot and RT-PCR were performed to evaluate changes in signaling pathways. Results showed that bFGF significantly increased mRNA expression of FGF receptor (FGFR)1 and FGFR2 at 10 min and increased expression of phosphorylated extracellular signal-regulated kinase (pERK1/pERK2) but not phosphorylated p38 mitogen-activated protein kinase (MAPK) or phosphorylated phosphatidylinositol 3-kinase (PI3K) within 30 min. This was followed by an increase of cyclooxygenase (COX)-2 mRNA and protein expression at 30 and 240 min, respectively. Mitogen-activated protein kinase kinase (MEK) inhibitor-PD98059 (10(-5) M) markedly suppressed bFGF-stimulated COX-2 expression and cell proliferation, but neither p38 MAPK inhibitor-SB203580 nor PI3K inhibitor-Wortmannin had any effect. Dexamethasone (10(-6)M) substantially reduced bFGF-stimulated ERK activation at 10 min, COX-2 mRNA and protein expression at 30 and 240 min, respectively, and prostaglandin E(2) synthesis at 8 h. Dexamethasone (10(-6) M) also significantly decreased mRNA expression of FGFR1 and FGFR2 at basal and bFGF-stimulated conditions at 10 min. This study indicated that bFGF-stimulated gastric epithelial RGM-1 cells proliferation via up-regulating FGFR1 and FGFR2, activating ERK1/ERK2 signal transduction pathway and COX-2 pathway. Dexamethasone significantly suppresses bFGF-stimulated RGM-1 cells proliferation in part via down-regulation of FGFR1/FGFR2, then decreasing bFGF-stimulated activation of ERK1/ERK2, followed by inhibition of COX-2 activation, and finally DNA synthesis.
Luo
Jiing-Chyuan
JC
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Lin
Hsiao-Yi
HY
Lu
Ching-Liang
CL
Wang
Lung-Yao
LY
Chang
Full-Young
FY
Lin
Han-Chieh
HC
Huang
Yi-Chen
YC
Ng
Ka-Man
KM
Chi
Chin-Wen
CW
Lee
Shou-Dong
SD
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000166:cytology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D003907:Dexamethasone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496350:Fgfr1 protein, rat; C496356:Fgfr2 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone