FGF-1 reverts epithelial-mesenchymal transition induced by TGF-β1 through MAPK/ERK kinase pathway
FGF-1 reverts epithelial-mesenchymal transition induced by TGF-β1 through MAPK/ERK kinase pathway
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DOI：
10.1152/ajplung.00070.2010
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发表时间：
2010-08-01
影响因子：
4.9
通讯作者：
Selman, Moises
中科院分区：
文献类型：
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作者：
Ramos, Carlos;Becerril, Carina;Selman, Moises
[10]拉莫斯C，贝塞里尔C，Montano M，Garcia-De-Alba C，Ramirez R，Pasta M，Pardo A，Selman M. FGF-1通过MAPK/ERK激酶途径逆转TGF-β 1诱导的上皮-间充质转化。Am J Physiol Lung Cell Mol Physiol 299：L222-L231，2010。首次发表于2010年5月21日; doi：10.1152/ajplung.00070.2010.-特发性肺纤维化（IPF）是一种进行性和致死性肺部疾病，其特征是成纤维细胞/肌成纤维细胞群的扩增和异常重塑。然而，这种疾病中间充质细胞的起源仍在争论中。最近的证据表明，上皮-间充质转化（EMT）主要由TGF-β 1诱导起着重要的作用，然而，关于相反的过程，间充质-上皮转化的研究很少。我们以前已经表明，成纤维细胞生长因子-1（FGF-1）抑制TGF-β 1的几种促纤维化作用。在这项研究中，我们研究了FGF-1对TGF-β 1诱导的EMT的影响。用TGF-β 1刺激A549和RLE-6 TN（人和大鼠）肺泡上皮样细胞系72小时，然后在TGF-β 1存在下，用FGF-1加肝素再培养48小时。TGF-β 1治疗后，上皮细胞获得了纺锤形间充质表型，E-钙粘蛋白和细胞角蛋白大量减少，同时诱导α-平滑肌肌动蛋白（通过实时PCR、Western印迹和免疫细胞化学测定）。FGF-1加肝素逆转了这些形态学变化，并将上皮和间充质标记物恢复到对照水平。选择性药理学抑制剂分析的信号通路显示TGF-β 1通过Smad通路诱导EMT，而FGF-1通过MAPK/ERK激酶通路逆转EMT，导致ERK-1磷酸化和Smad 2去磷酸化。这些发现表明，TGF-β 1诱导的EMT被FGF-1逆转，并提出了针对IPF中该过程的治疗方法。
Ramos C, Becerril C, Montano M, Garcia-De-Alba C, Ramirez R, Checa M, Pardo A, Selman M. FGF-1 reverts epithelial-mesenchymal transition induced by TGF-beta 1 through MAPK/ERK kinase pathway. Am J Physiol Lung Cell Mol Physiol 299: L222-L231, 2010. First published May 21, 2010; doi:10.1152/ajplung.00070.2010.-Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition (EMT) induced primarily by TGF-beta 1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 (FGF-1) inhibits several profibrogenic effects of TGF-beta 1. In this study, we examined the effects of FGF-1 on TGF-beta 1-induced EMT. A549 and RLE-6TN (human and rat) alveolar epithelial-like cell lines were stimulated with TGF-beta 1 for 72 h, and then, in the presence of TGF-beta 1, were cultured with FGF-1 plus heparin for an additional 48 h. After TGF-beta 1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of alpha-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. FGF-1 plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-beta 1 induces EMT through Smad pathway, while reversion by FGF-1 occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-beta 1-induced EMT is reversed by FGF-1 and suggest therapeutic approaches to target this process in IPF.