title: Inhibitory effects of dexamethasone on hepatocyte growth factor-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.
abstract: We investigated the effects of dexamethasone on hepatocyte growth factor (HGF)-induced DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. Isolated hepatocytes were cultured at a density of 3.3 × 10(4) cells/cm(2) in Williams' medium E containing 5% newborn bovine serum and various concentrations of dexamethasone for 1, 2, and 3 h. After a 3-h attachment period, the medium was then changed, and cells were cultured in serum-free dexamethasone (10(-10) M)-containing Williams' medium E with or without glucocorticoid receptor antagonists. After addition of dexamethasone to the culture medium, the growth-stimulating effects of HGF (5 ng/mL) on the primary cultured hepatocytes were time- and dose-dependently inhibited. The mineralcorticoid aldosterone (10(-7) M) did not produce the same growth-inhibitory effects as dexamethasone (10(-8) M). The inhibitory effects of dexamethasone were reversed by treatment with the glucocorticoid-receptor antagonist mifepristone (RU486, 10(-6) M) or a monoclonal antibody against glucocorticoid receptor (100 ng/mL). In addition, the growth-inhibitory dose of dexamethasone did not affect HGF-induced receptor tyrosine kinase and extracellular signal-regulated kinase 2 phosphorylation. These results indicate that dexamethasone dose-dependently delays and inhibits HGF-induced DNA synthesis and proliferation through its own intracellular receptor in primary cultures of adult rat hepatocytes.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Sakado, Japan. mkimura@josai.ac.jp
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Kimura
authors.forename: Hajime
authors.initials: H
authors.lastname: Moteki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ogihara
mesh_terms: D000818:Animals; D002417:Cattle; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects*; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D017228:Hepatocyte Growth Factor; D003907:Dexamethasone; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1