Transforming growth factor β signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts -: TGFβ signal transduction during transdifferentiation of hepatic stellate cells
Transforming growth factor β signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts -: TGFβ signal transduction during transdifferentiation of hepatic stellate cells
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DOI：
10.1016/s0014-5793(01)02656-4
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发表时间：
2001-07-27
期刊：
影响因子：
3.5
通讯作者：
Gressner, AM
中科院分区：
文献类型：
--
作者：
Dooley, S;Delvoux, B;Gressner, AM
据目前所知，转化生长因子β信号在肝纤维化的形成中起着强制性的作用，各种旨在影响转化生长因子β系统的分子干预措施被成功地用于抑制肝纤维化的发生。活化的肝星状细胞(HSC)是肝损伤过程中产生细胞外基质蛋白的主要来源之一，是转化生长因子的重要来源。我们之前已经证明，这种细胞类型的转化生长因子β反应在转分化过程中受到调节。这项工作描述了在静止的HSC和转分化的肌成纤维细胞(MFB)中，转化生长因子β下游介质Smads的激活。在这一过程中，所有Smad的表达水平基本保持不变。HSC对转化生长因子β的反应，例如，诱导α2(I)胶原的表达，是通过Smad2和Smad3的磷酸化以及随后含有Smad的复合体的核移位来介导的。在转分化的MFB中，无论是转化生长因子β依赖的还是内源性磷酸化的Smad2/3都没有检测到类似的量，这表明转化生长因子β敏感性的丧失。Smad7在HSC中的异位表达抑制了Smad2的磷酸化，抑制了转化生长因子β的反应。在转分化的MFB中，表达固有活性的转化生长因子β受体I，而不是用转化生长因子β1处理，导致转化生长因子β反应启动子的转录激活，从而表明转化生长因子β信号转导完全恢复。我们的数据表明，与假设的持续自分泌转化生长因子β信号转导机制相反，必须区分HSC激活的早期和晚期，这对于抗纤维化治疗是重要的。(C)2001年欧洲生化学会联合会。爱思唯尔科学公司出版。版权所有。
To current knowledge, transforming growth factor beta (TGF beta) signaling is mandatory to establish liver fibrosis and various molecular interventions designed to affect the TGF beta system were successfully used to inhibit fibrogenesis. Activated hepatic stellate cells (HSC), which are one important source of TGF, are the major producers of extracellular matrix proteins in liver injury. We have previously shown that the TGF beta response of this cell type is modulated during the transdifferentiation process. This work delineates the activation of TGF beta downstream mediators, the Smads, in quiescent HSC and transdifferentiated myofibroblasts (MFB). The expression level of all Smads remained largely unchanged during this process. The response of HSC to TGF beta, leading to, e.g., induction of alpha2 (I) collagen expression, is mediated by phosphorylation of Smad2 and Smad3 and subsequent nuclear translocation of a Smad containing complex. Neither TGF beta -dependent nor endogenously phosphorylated Smad2/3 was detectable in comparable amounts in transdifferentiated MFB, indicating loss of TGF beta sensitivity. Ectopic expression of Smad7 in HSC led to inhibition of Smad2 phosphorylation and abrogated TGF beta response. In transdifferentiated MFB, expression of a constitutively active TGF beta receptor I, but not treatment with TGF beta1, resulted in transcriptional activation of a TGF beta responsive promoter, thereby demonstrating completely restored TGF beta signal transduction. Our data indicate that in contrast to a postulated mechanism of enduring autocrine TGF beta signal transduction, early and late stages of HSC activation have to be distinguished, which is of importance for antifibrotic therapies. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.