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标题：Serotonin 5-HT_2B Receptor-Stimulated DNA Synthesis and Proliferation Are Mediated by Autocrine Secretion of Transforming Growth Factor-α in Primary Cultures of Adult Rat Hepatocytes
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作者：Kota Naito ; Hajime Moteki ; Mitsutoshi Kimura 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2016
卷号：39
期号：4
页码：570-577
DOI：10.1248/bpb.b15-00923
出版社：The Pharmaceutical Society of Japan
摘要：The mechanism of serotonin 5-HT₂ receptor subtype-stimulated DNA synthesis and proliferation was investigated in primary cultures of adult rat hepatocytes to elucidate the intracellular signal transduction pathways. DNA synthesis and proliferation were detected in hepatocyte parenchymal cells grown in serum-free, defined medium containing 5-HT (10⁻⁶ M) or the selective 5-HT_2B receptor agonist BW723C86 (10⁻⁶ M). In addition, exogenous transforming growth factor (TGF)-α (1.0 ng/mL) significantly increased hepatocyte DNA synthesis and proliferation, which reached plateau after 4 h of culture. Use of blocking monoclonal antibodies demonstrated that TGF-α, but not insulin-like growth factor-I, was involved in hepatocyte proliferation mediated by 5-HT or BW723C86. TGF-α levels in the culture medium increased significantly versus baseline within 5 min in response to 5-HT (10⁻⁶ M) or BW723C86 (10⁻⁶ M), and the maximum TGF-α level (30 pg/mL) was reached 10 min after 5-HT or BW723C86 stimulation. Secretion of TGF-α into the culture medium was inhibited by addition of the selective phospholipase C (PLC) inhibitor, U-73122 (10⁻⁶ M), or somatostatin (10⁻⁷ M). These results indicate that the proliferative mechanism of action of 5-HT is mediated mainly through a 5-HT_2B receptor/Gq/PLC-stimulated increase in autocrine secretion of TGF-α from primary cultured hepatocytes.