Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat
Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat
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DOI：
10.1053/jhep.2002.34741
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发表时间：
2002-08-01
期刊：
影响因子：
13.5
通讯作者：
Gaudio, E
中科院分区：
文献类型：
--
作者：
Alvaro, D;Onori, P;Gaudio, E
本研究旨在探讨雌激素刺激胆管细胞增殖的细胞内信号通路。我们通过评估总的和磷酸化的丝裂原活化蛋白激酶（MAPK）亚型p44/p42（例如，细胞外信号调节激酶[ERK] 1/2）、类固醇受体辅激活剂Src和Shc（Src同源/胶原蛋白）。该研究在3周龄的胆管结扎（BDL）大鼠、用抗雌激素、他莫昔芬或Ici 182，780处理的BDL大鼠和正常对照大鼠中进行。在存在或不存在他莫昔芬、Ici 182，780、ERK或Src抑制剂的情况下，用17113雌二醇处理的正常纯化胆管细胞中也评价了增殖。胆管结扎后，胆管细胞增殖与磷酸化（p）-ERK 1/2的显著免疫组化核阳性相关，其可通过他莫昔芬或Ici 182，780体内治疗抑制。总的和p-ERK 1/2，和Shc在胆管细胞中分离BDL大鼠的蛋白表达显着增加与对照组相比，并在体内治疗与抗雌激素抑制。在体外，17 β雌二醇诱导的离体正常胆管细胞增殖与p-ERK 1/2、Src和Shc蛋白表达的增加相关（P <0.01）。ER（Ici 182，780）、ERK（U 0125）和Src（PP 2）的特异性抑制剂抑制体外17 β雌二醇诱导的胆管细胞增殖。总之，这项研究表明，雌激素诱导胆管细胞增殖激活Src/Shc/ERK途径。这可能表明，ER，ERK，和/或Src的药理学调节可以提出用于治疗人类病理学特征的胆管细胞增殖失调。
The aim of this study was to explore the intracellular signaling pathways involved in the stimulatory effects of estrogens on cholangiocyte proliferation. We investigated the tyrosine kinase-receptor pathway by evaluating the protein expression of total and phosphorylated mitogen-activated protein kinase (MAPK) isoform p44/p42 (e.g., extracellular signal-regulated kinase [ERK] 1/2), the steroid-receptor coactivator Src and Shc (Src-homology/collagen protein). The study was performed in 3-week-old bile duct-ligated (BDL) rats, BDL rats treated with the antiestrogens, tamoxifen or Ici 182,780, and normal control rats. Proliferation was also evaluated in normal purified cholangiocytes treated with 17113 estradiol in the presence or absence of tamoxifen, Ici 182,780, ERK, or Src inhibitors. After bile duct ligation, cholangiocyte proliferation was associated with a marked immunohistochemical nuclear positivity for phosphorylated (p)-ERK1/2, which was inhibited by in vivo treatment with tamoxifen or Ici 182,780. Protein expression of total and p-ERK1/2, and Shc in cholangiocytes isolated from BDL rats was markedly increased compared with controls and was inhibited by in vivo treatment with antiestrogens. In vitro, 17beta estradiol-induced proliferation of isolated normal cholangiocyte was associated with increased (P < .01) protein expression of p-ERK1/2, Src, and Shc. Specific inhibitors of ER (Ici 182,780), ERK (U0125), and Src (PP2) inhibited in vitro 17beta estradiol-induced cholangiocyte proliferation. In conclusion, this study showed that estrogens induced cholangiocyte proliferation by activating the Src/Shc/ERK pathway. This might suggest that pharmacologic modulation of ER, ERK, and/or Src could be proposed for the treatment of human pathology characterized by dysregulation of cholangiocyte proliferation.