Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis.
Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis.
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DOI：
10.1038/srep16552
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发表时间：
2015-11-12
影响因子：
4.6
通讯作者：
Bian H
中科院分区：
文献类型：
--
作者：
Li HY;Ju D;Zhang DW;Li H;Kong LM;Guo Y;Li C;Wang XL;Chen ZN;Bian H
通过转化生长因子-β1（TGF-β1）的激活启动HBV相关的纤维化。 -CD147通过HSC的激活促进肝纤维发生。用于评估信号循环中分子的激活和细胞收缩测定法，以检测CD147过表达的HSC迁移和收缩。和染色质免疫沉淀。迁移和加速TGF-β1诱导的细胞收缩。通过ERK1/2和SP1，上调α-SMA，胶原蛋白I和TGF-β1合成TGF-β1-CD147循环在确定TGF-β受体抑制剂和抗CD147抗体的HSC激活和组合中起关键作用可能会逆转纤维化。
Activation of hepatic stellate cells (HSCs) by transforming growth factor-β1 (TGF-β1) initiates HBV-associated fibrogenesis. The mechanism of TGF-β1 modulating HSC activation is not fully uncovered. We hypothesized a positive feedback signaling loop of TGF-β1-CD147 promoting liver fibrogenesis by activation of HSCs. Human HSC cell line LX-2 and spontaneous liver fibrosis model derived from HBV transgenic mice were used to evaluate the activation of molecules in the signaling loop. Wound healing and cell contraction assay were performed to detect the CD147-overexpressed HSC migration and contraction. The transcriptional regulation of CD147 by TGF-β1/Smad4 was determined using dual-luciferase reporter assay and chromatin immunoprecipitation. We found that a positive reciprocal regulation between TGF-β1 and CD147 mediated HSC activation. CD147 over-expression promoted HSC migration and accelerated TGF-β1-induced cell contraction. Phosphorylation of Smad2 and Smad3 in cooperation with Smad4 mediated the TGF-β1-regulated CD147 expression. Smad4 activated the transcription by direct interaction with CD147 promoter. Meanwhile, CD147 modulated the activated phenotype of HSCs through the ERK1/2 and Sp1 which up-regulated α-SMA, collagen I, and TGF-β1 synthesis. These findings indicate that TGF-β1-CD147 loop plays a key role in regulating the HSC activation and combination of TGF-β receptor inhibitor and anti-CD147 antibody might be promised to reverse fibrogenesis.