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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Dexamethasone Inhibits Epidermal Growth Factor-Stimulated Gastric Epithelial Cell Proliferation

Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (J.-C.L., F.-Y.C., C.-L.L., C.-Y.C., S.-D.L.); Department of Medical Research and Education, Taipei Veterans General Hospital and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan (C.-W.C.); and Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital and Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (H.-Y.L.)

Epidermal growth factor (EGF) is essential to heal gastric ulcers, whereas glucocorticoid delays rat gastric ulcer healing. We found that dexamethasone inhibited EGF-stimulated rat gastric epithelial cell (RGM-1) proliferation by cell count and DNA synthesis analysis of flow cytometry and attempted to elucidate the possible mechanistic pathway via Western blot analysis. EGF (10 ng/ml) treatment for 24 h significantly increased RGM-1 cell proliferation, and dexamethasone (10^–8 and 10^–6 M) markedly suppressed EGF-stimulated cell proliferation. Western blotting results demonstrated that the phosphorylated extracellular signal-regulated kinase (pERK) (pERK1/pERK2) significantly increased at 10 min after EGF treatment. This was followed by increase of cyclooxygenase (COX)-2 expression at 3 h after EGF treatment. The continued increase of COX-2 (up to 18 h) resulted in increased intracellular prostaglandin E₂ and cyclin D1 expression significantly after 8 and 12 h of EGF treatment. Dexamethasone substantially reduced EGF-stimulated COX-2 expression at 3 and 6 h and cyclin D1 expression at 8 and 12 h. Pretreatment of RGM-1 cells with dexamethasone or 2'-amino-3'-methoxyflavone (PD98059)-mitogen-activated protein kinase kinase inhibitor (5 x 10^–5 M) significantly reduced EGF-stimulated pERK1/pERK2 expression. Simultaneous treatment of RGM-1 cells with PD98059 and EGF also markedly decreased EGF-stimulated COX-2 expression at 6 h. These findings indicate that dexamethasone significantly suppresses EGF-stimulated gastric epithelial cell proliferation, and one of the pathways involved is via inhibiting activation of ERK1/ERK2, followed by inhibition of COX-2, cyclin D1 expression, and finally DNA synthesis.

Address correspondence to: Dr. Full-Young Chang, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Rd., Section 2, Taipei, Taiwan 11217. E-mail: changfy{at}vghtpe.gov.tw