Impaired Smad7-Smurf-mediated negative regulation of TGF-β signaling in scleroderma fibroblasts
Impaired Smad7-Smurf-mediated negative regulation of TGF-β signaling in scleroderma fibroblasts
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DOI：
10.1172/jci200416269
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发表时间：
2004-01-01
影响因子：
15.9
通讯作者：
Tamaki, K
中科院分区：
文献类型：
--
作者：
Asano, Y;Ihn, H;Tamaki, K
TGF-β 1对间充质细胞的主要作用是刺激ECM合成。以往的报道表明自分泌TGF-β环在硬皮病发病机制中的重要性。在这项研究中，我们专注于Smad 7和Smurfs，负调节TGF-β信号的主要分子，以进一步了解硬皮病中的自分泌TGF-β环。与正常成纤维细胞相比，硬皮病成纤维细胞在体内和体外表现出增加的Smad 7水平。Smad 7与TGF-β受体组成性地形成复合物，并且在硬皮病成纤维细胞中，Smad 7对人α 2（I）胶原和3 TP-lux的启动子活性的抑制作用完全受损。此外，与正常成纤维细胞相比，硬皮病成纤维细胞中I型TGF-β受体的蛋白质稳定性显著增加。正常和硬皮病成纤维细胞之间的Smurf 1和Smurf 2水平没有显著差异，并且瞬时过表达的Smurf 1和/或Smurf 2不影响硬皮病成纤维细胞中TGF-β受体I型蛋白水平。这些结果表明，受损的Smad 7-Smurf介导的对TGF-β信号传导的抑制作用可能有助于维持硬皮病成纤维细胞中的自分泌TGF-β环。据我们所知，这是第一份关于纤维化疾病中TGF-β信号负调控紊乱的报告。
The principal effect of TGF-beta1 on mesenchymal cells is its stimulation of ECM synthesis. Previous reports indicated the significance of the autocrine TGF-beta loop in the pathogenesis of scleroderma. In this study, we focused on Smad7 and Smurfs, principal molecules in the negative regulation of TGF-beta signaling, to further understand the autocrine TGF-beta loop in scleroderma. Scleroderma Fibroblasts exhibited increased Smad7 levels compared with normal fibroblasts in vivo and in vitro. Smad7 constitutively formed a complex with the TGF-beta receptors, and the inhibitory effect of Smad7 on the promoter activity of human alpha2(I) collagen and 3TP-lux was completely impaired in scleroderma fibroblasts. Furthermore, the protein stability of TGF-beta receptor type I was significantly increased in scleroderma fibroblasts compared with normal fibroblasts. There was no significant difference in Smurf1 and Smurf2 levels between normal and scleroderma fibroblasts, and the transiently overexpressed Smurf1 and/or Smurf2 did not affect TGF-beta receptor type I protein levels in scleroderma fibroblasts. These results indicate that the impaired Smad7-Smurf-mediated inhibitory effect on TGF-beta signaling might contribute to maintaining the autocrine TGF-beta loop in scleroderma fibroblasts. To our knowledge, this is the first report of a disturbed negative regulation of TGF-beta signaling in fibrotic disorders.