ID JOS-13473506-109_618
著者：名前 著者：別形式 Kimura, Mitsutoshi / Okamoto, Hiroshi / Natume, Hideshi / Ogihara, Masahiko
著者：カナ 著者：所属 城西大学薬学部 / 城西大学薬学部 / 城西大学薬学部 / 城西大学薬学部
著者：所属(別形式） Josai University, Faculty of Pharmaceutical Sciences, Department of Clinical Pharmacology / Josai University, Faculty of Pharmaceutical Sciences, Department of Clinical Pharmacology / Josai University, Faculty of Pharmaceutical Sciences, Department of Pharmaceutics / Josai University, Faculty of Pharmaceutical Sciences, Department of Clinical Pharmacology
著者版フラグ author
出版地 東京
出版者 日本薬理学会
出版者：カナ ニホンヤクリガッカイ
出版者：別名 The Japanese Pharmacological Society
NCID AA11806667
冊子ISSN 13478648
電子ISSN 13478648
掲載誌名 巻 109
号 4
刊行年月 2009-04
開始ページ 618
終了ページ 629
コンテンツ作成日 2009-02-22
コンテンツ登録日 2011-02-16
識別番号：URI 識別番号：DOI info:doi/10.1254/jphs.08338FP
識別番号：DOI（リンク） 抄録 To elucidate the mechanism of action of prostaglandin I2 (PGI2) and carbaprostacyclin we studied their effect on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. Hepatocyte parenchymal cells, maintained in a serum-free, defined medium, synthesized DNA and proliferated in the presence of PGI2 (10-8 M) or carbaprostacyclin (10-9 M) in a time- and dose-dependent manner. PGI2 was less potent than carbaprostacyclin in stimulating hepatocyte mitogenesis. These effects of PGI2 and carbaprostacyclin were abolished by treatment with a specific IP receptor antagonist, CAY10441 (10-9 ~10-7 M), and by the thromboxane A2 receptor agonist, U46619 (10-7 M). Hepatocyte mitogenesis induced by the IP receptor agonists was almost completely blocked by specific inhibitors of growth-related signal transducers such as AG1478 (5 × 10-7 M), LY294002 (10-7 M), PD98059 (10-6 M), and rapamycin (10 ng/ml). In addition, PGI2 or carbaprostacyclin significantly increased the kinase activity of a (p175 kDa) receptor tyrosine kinase and the phosphorylation of p42 kDa mitogen-activated protein (MAP) kinase. Addition of a monoclonal antibody against transforming growth factor (TGF)-α, but not insulin-like growth factor-I, to the culture dose-dependently inhibited the PGI2- or carbaprostacyclin-induced hepatocyte mitogenesis. These results suggest that the IP receptor agonist-induced hepatocyte mitogenesis is mediated by autocrine secretion of TGF-α followed by activation of a receptor tyrosine kinase/MAP kinase pathway.
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