Induction of Fas receptor and Fas ligand by nodularin is mediated by NF-κB in HepG2 cells
Induction of Fas receptor and Fas ligand by nodularin is mediated by NF-κB in HepG2 cells
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DOI：
10.1016/j.taap.2011.01.009
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发表时间：
2011-03-15
影响因子：
3.8
通讯作者：
Bai, Yansheng
中科院分区：
文献类型：
--
作者：
Feng, Gong;Li, Ying;Bai, Yansheng
节球藻毒素是一种具有多种功能的天然毒素，包括蛋白磷酸酶1和2A的抑制剂以及肿瘤的引发剂和促进剂。节球藻毒素的一个独特特征是这种化学物质是一种肝毒素。接触后可在肝脏内蓄积，导致肝细胞严重损伤，如细胞凋亡。Fas受体（Fas）和Fas配体（FasL）系统是启动细胞凋亡的重要信号网络。在本研究中，我们研究了节球藻毒素是否可以诱导Fas和FasL在HepG 2细胞中的表达，HepG 2细胞是一种用于研究人肝细胞的体外模型。我们的数据表明，节球藻毒素诱导Fas和FasL的表达，在mRNA和蛋白水平，在时间和剂量依赖性的方式。在诱导Fas和FasL表达的浓度和作用时间范围内，节球藻素诱导细胞凋亡。FasL的中和抗体减少了nodularin诱导的细胞凋亡。进一步的研究表明，节球藻毒素可促进NF-κ B B的核转位和p65亚基的活化。通过应用靶向p65的siRNA，敲低HepG 2细胞中的p65，我们成功地削弱了节球藻毒素对NF-κ B的激活。在这些p65基因敲低的细胞中，我们观察到Fas和FasL的表达和由节球藻素诱导的凋亡显著减少。这些结果表明，节球藻毒素诱导HepG 2细胞Fas和FasL表达，从而诱导细胞凋亡是通过NF-κ B途径实现的。(C)2011 Elsevier Inc. All rights reserved.
Nodularin is a natural toxin with multiple features, including inhibitor of protein phosphatases 1 and 2A as well as tumor initiator and promoter. One unique feature of nodularin is that this chemical is a hepatotoxin. It can accumulate into the liver after contact and lead to severe damage to hepatocyte, such as apoptosis. Fas receptor (Fas) and Fas ligand (FasL) system is a critical signaling network triggering apoptosis. In current study, we investigated whether nodularin can induce Fas and FasL expression in HepG2 cell, a well used in vitro model for the study of human hepatocytes. Our data showed nodularin induced Fas and FasL expression, at both mRNA and protein level, in a time- and dose-dependent manner. We also found nodularin induced apoptosis at the concentration and incubation time that Fas and FasL were significantly induced. Neutralizing antibody to FasL reduced nodularin-induced apoptosis. Further studies demonstrated that nodularin promoted nuclear translocation and activation of p65 subunit of NF-kappa B. By applying siRNA targeting p65, which knocked down p65 in HepG2 cells, we successfully impaired the activation of NF-kappa B by nodularin. In these p65 knockdown cells, we observed that Fas and FasL expression and apoptosis induced by nodularin were significantly reduced. These findings suggest the induction of Fas and FasL expression and thus cell apoptosis in HepG2 cells by nodularin is mediated through NF-kappa B pathway. (C) 2011 Elsevier Inc. All rights reserved.