TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts
TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts
复制标题
DOI：
10.1016/j.phrs.2008.02.001
复制
发表时间：
2008-04-01
影响因子：
9.3
通讯作者：
Vancheri, Carlo
中科院分区：
文献类型：
--
作者：
Caraci, Filippo;Gili, Elisa;Vancheri, Carlo
已知转化生长因子-α1(TGF-β1)可诱导人肺成纤维细胞向肌成纤维细胞转化，这是特发性肺纤维化发病机制中的主要事件。我们发现转化生长因子-β1(10 ng/ml)作用于人肺成纤维细胞24小时可诱导α-平滑肌动蛋白(SMA)的表达和胶原的产生。这些作用被丝裂原活化蛋白激酶(MAPK)通路的特异性抑制剂PD98059所消除。转化生长因子-β1处理激活了MAPK通路，表现为暴露30分钟后细胞外调节蛋白激酶(ERK)1/2的磷酸化增加。转化生长因子-β1还可增加丝氨酸-9磷酸化失活形式的糖原合成酶-3β(GSK-3β)的表达，这种作用可被PD98059大大减弱。共聚焦显微镜和核蛋白分析显示，在加入转化生长因子-β1后2小时，人肺成纤维细胞中的β-连环蛋白发生了核转位。在这个时候，转化生长因子-β1也增加了β-连环蛋白的总水平，这一作用被PD98059阻止。与转化生长因子-β1类似，GSK-3β抑制剂氯化锂(10 MM)可增加人肺成纤维细胞中β-连环蛋白的总水平，促进α-SMA的表达和胶原合成。本研究表明，转化生长因子-β1通过ERK1/2激活、GSK-3β抑制和核β-连环蛋白转位诱导人肺成纤维细胞α-SMA表达和胶原生成。SiRNAs沉默β-catenin能够阻止转化生长因子-β1诱导成纤维细胞α-SMA表达的证据进一步支持GSK-3β/β-catenin通路在特发性肺纤维化发病机制中的作用的假说。(C)2008爱思唯尔有限公司。保留所有权利。
Transforming growth factor-alpha 1 (TGF-beta 1) is known to induce the transition of human lung fibroblasts to myofibroblasts, a primary event in the pathogenesis of idiopathic pulmonary fibrosis. The molecular pathways involved in myofibroblast transformation are only partially identified.We found that a 24-h treatment with TGF-beta 1 (10 ng/ml) induced alpha-smooth actin (SMA) expression and collagen production in human lung fibroblasts. These effects were abrogated by PD98059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway. TGF-beta 1 treatment activated the MAPK pathway, as shown by an increased phosphorylation of extracellular-regulated kinases (ERK)1/2 after 30 min of exposure. TGF-beta 1 also increased the expression of the Ser-9-phosphorylated inactive form of glycogen synthase kinase-3 beta (GSK-3 beta), an effect that was largely attenuated by PD98059. A nuclear translocation of beta-catenin in human lung fibroblasts was observed 2h after TGF-beta 1 addition both by confocal microscopy and nuclear protein analysis. At this time, TGF-beta 1 also increased the total levels of beta-catenin, an effect that was preventedby PD98059. Similarly to TGF-beta 1, the GSK-3 beta inhibitor lithium chloride (10 mM), increased the total levels of beta-catenin and promoted alpha-SMA expression and collagen production.This study demonstrates that TGF-beta 1 induces alpha-SMA expression and collagen production in human lung fibroblasts via ERK1/2 activation, GSK-3 beta inhibition and nuclear beta-catenin translocation. The evidence that the silencing of beta-catenin by siRNAs was able to prevent the induction of alpha-SMA expression in TGF-beta 1-treated fibroblasts further supports the hypothesis of a contribution of the GSK-3 beta/beta-catenin pathway in the pathogenesis of idiopathic pulmonary fibrosis. (C) 2008 Elsevier Ltd. All rights reserved.