A crosstalk between the Smad and JNK signaling in the TGF-β-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells.
A crosstalk between the Smad and JNK signaling in the TGF-β-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells.
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DOI：
10.1371/journal.pone.0032009
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Liu Q;Zhang Y;Mao H;Chen W;Luo N;Zhou Q;Chen W;Yu X
转化生长因子β（TGF-β）通过Smad和JNK信号通路诱导上皮-间充质转化（EMT）过程。然而，这些通路在TGF-β1诱导的大鼠腹膜间皮细胞（RPMCs）EMT中如何相互作用尚不清楚。在此，我们发现，通过引入显性负性JNK 1基因抑制JNK活化，减弱TGF-β1下调的E-cadherin表达，以及TGF-β1上调的α-SMA、胶原I和派-1表达，从而抑制原代培养的RPMC中的EMT。此外，TGF-β1在RPMC中诱导双峰JNK活化，在处理后10分钟和12小时达到峰值。此外，通过引入Smad 3突变体来抑制Smad 3活化减轻了TGF-β1诱导的RPMC中JNK 1活化的第二波，但不是第一波。抑制JNK 1活化可抑制TGF-β1诱导的Smad 3活化和核转位，抑制TGF-β1诱导的JNK第二波活化可显著降低TGF-β1诱导的RPMC EMT。这些数据表明在TGF-β1诱导的RPMC中EMT和纤维化过程中JNK 1和Samd 3通路之间存在串扰。因此，我们的研究结果可能为了解TGF-β1相关的JNK和Smad信号通路在纤维化发生发展中的调控提供新的见解。
Transforming growth factor β (TGF-β) induces the process of epithelial-mesenchymal transition (EMT) through the Smad and JNK signaling. However, it is unclear how these pathways interact in the TGF-β1-induced EMT in rat peritoneal mesothelial cells (RPMCs). Here, we show that inhibition of JNK activation by introducing the dominant-negative JNK1 gene attenuates the TGF-β1-down-regulated E-cadherin expression, and TGF-β1-up-regulated α-SMA, Collagen I, and PAI-1 expression, leading to the inhibition of EMT in primarily cultured RPMCs. Furthermore, TGF-β1 induces a bimodal JNK activation with peaks at 10 minutes and 12 hours post treatment in RPMCs. In addition, the inhibition of Smad3 activation by introducing a Smad3 mutant mitigates the TGF-β1-induced second wave, but not the first wave, of JNK1 activation in RPMCs. Moreover, the inhibition of JNK1 activation prevents the TGF-β1-induced Smad3 activation and nuclear translocation, and inhibition of the TGF-β1-induced second wave of JNK activation greatly reduced TGF-β1-induced EMT in RPMCs. These data indicate a crosstalk between the JNK1 and Samd3 pathways during the TGF-β1-induced EMT and fibrotic process in RPMCs. Therefore, our findings may provide new insights into understanding the regulation of the TGF-β1-related JNK and Smad signaling in the development of fibrosis.
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