A Crosstalk between the Smad and JNK Signaling in the TGF-β-Induced Epithelial-Mesenchymal Transition in Rat Peritoneal Mesothelial Cells

作者：Liu, Qinghua^*; Zhang, Yu; Mao, Haiping; Chen, Wei; Luo, Ning; Zhou, Qin; Chen, Wenfang; Yu, Xueqing

来源：PLos One, 2012, 7(2): e32009.

DOI：10.1371/journal.pone.0032009

• GROWTH-FACTOR-BETA
• PROTEIN-KINASE PATHWAYS
• HEPATIC STELLATE CELLS
• HUMAN LUNG FIBROBLASTS
• PAI-1 GENE-EXPRESSION
• MEDIATED TRANSCRIPTION
• INDEPENDENT PATHWAYS
• MESANGIAL CELLS
• TGF-BETA-1
• FIBROSIS

Transforming growth factor beta (TGF-beta) 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-beta 1-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-beta 1-down-regulated E-cadherin expression, and TGF-beta 1-up-regulated alpha-SMA, Collagen I, and PAI-1 expression, leading to the inhibition of EMT in primarily cultured RPMCs. Furthermore, TGF-beta 1 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-beta 1-induced second wave, but not the first wave, of JNK1 activation in RPMCs. Moreover, the inhibition of JNK1 activation prevents the TGF-beta 1-induced Smad3 activation and nuclear translocation, and inhibition of the TGF-gamma 1-induced second wave of JNK activation greatly reduced TGF-beta 1-induced EMT in RPMCs. These data indicate a crosstalk between the JNK1 and Samd3 pathways during the TGF-beta 1-induced EMT and fibrotic process in RPMCs. Therefore, our findings may provide new insights into understanding the regulation of the TGF-beta 1-related JNK and Smad signaling in the development of fibrosis.

• 出版日期2012-2-27
• 单位中山大学