Hasegawa K, Kar S, Carr B I
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15213.
J Cell Physiol. 1994 Feb;158(2):215-22. doi: 10.1002/jcp.1041580202.
Epidermal growth factor and transforming growth factor alpha stimulated DNA synthesis in primary cultures of adult rat hepatocytes. Neurotensin amplified epidermal growth factor-stimulated or transforming growth factor alpha-stimulated DNA synthesis by three- to eightfold. Neurotensin by itself did not stimulate DNA synthesis. Amplification of DNA synthesis by neurotensin was observed as low as 10(-10) M, and it was increased in a dose-dependent manner with maximal effects at 10(-8) M. These results were obtained when hepatocytes were cultured in Williams' medium E, but not in Leibovitz L-15 medium, suggesting that a minor component(s) in the medium is required for hepatocytes to fully respond to neurotensin. Neurotensin effect on DNA synthesis was observed not only in normal rat hepatocytes but also in partially hepatectomized rat hepatocytes, although its effect was stronger in normal hepatocytes. Amplified DNA synthesis was inhibited by transforming growth factor beta. Secondary mitogens (co-mitogens) such as insulin, vasopressin, or angiotensin II interacted additively with low concentrations of epidermal growth factor as well as with neurotensin. Neurotensin-related peptides such as kinetensin or neuromedin-N, which was released from blood plasma by pepsin digestion, did not have this amplifying effect on DNA synthesis at any concentrations tested. Neurotensin mRNA was found in several organs including brain and intestine, but not liver. These results suggest that neurotensin can be regarded as a new secondary mitogen and that it may be involved in cell proliferation, including regenerating liver as a gastrointestinal hormone and/or a neurotransmitter.
表皮生长因子和转化生长因子α可刺激成年大鼠肝细胞原代培养物中的DNA合成。神经降压素可将表皮生长因子刺激的或转化生长因子α刺激的DNA合成放大3至8倍。神经降压素自身并不刺激DNA合成。在低至10^(-10)M的浓度下即可观察到神经降压素对DNA合成的放大作用，且其作用呈剂量依赖性增加，在10^(-8)M时达到最大效应。这些结果是在肝细胞于Williams' E培养基中培养时获得的，但在Leibovitz L-15培养基中未获得，这表明培养基中的一种次要成分是肝细胞对神经降压素充分应答所必需的。不仅在正常大鼠肝细胞中，而且在部分肝切除的大鼠肝细胞中都观察到了神经降压素对DNA合成的作用，尽管其在正常肝细胞中的作用更强。转化生长因子β可抑制放大的DNA合成。胰岛素、血管加压素或血管紧张素II等二级促有丝分裂原（共促有丝分裂原）与低浓度的表皮生长因子以及神经降压素呈相加作用。胃蛋白酶消化从血浆中释放的激肽释放酶或神经介素-N等神经降压素相关肽在任何测试浓度下对DNA合成均无此放大作用。在包括脑和肠在内的多个器官中发现了神经降压素mRNA，但在肝脏中未发现。这些结果表明，神经降压素可被视为一种新的二级促有丝分裂原，并且它可能作为一种胃肠激素和/或神经递质参与包括肝再生在内的细胞增殖。
