Hepatic stellate cells lack AP-1 responsiveness to electrophiles and phorbol 12-myristate-13-acetate.
Hepatic stellate cells lack AP-1 responsiveness to electrophiles and phorbol 12-myristate-13-acetate.
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DOI：
10.1016/j.bbrc.2004.07.180
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发表时间：
2004-09
影响因子：
3.1
通讯作者：
J. Reichard;D. Petersen
中科院分区：
文献类型：
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作者：
J. Reichard;D. Petersen
星状细胞促纤维化基因的诱导和转分化是肝纤维化的中心事件。氧化应激通过共享的激酶信号传导途径被认为是转录因子Nrf 2和AP-1的激活因子，据称这也有助于星状细胞活化。本研究探讨了氧化应激的作用，ARE和TRE-regulated基因诱导在离体肝星状细胞。使用由ARE嵌入的TRE组成的人Nqo 1启动子的一部分，证明了当ARE负责介导响应于亲电试剂4-HNE和tBHQ的诱导型基因表达时，TRE对亲电试剂或PMA的诱导是抗性的。结果表明，星状细胞具有被鉴定为JunB、JunD、Fra 1和Fra 2的核TRE结合蛋白，这些蛋白不受亲电试剂或PMA处理的影响。这份报告表明，在对比的ARE，TRE及其结合同源AP-1不介导独立的基因诱导肝星状细胞。考虑到AP-1在介导促纤维化基因表达中的假定重要性，该观察结果是重要的。
Stellate cell profibrotic gene induction and transdifferentiation are central events in liver fibrosis. Oxidative stress has been implicated as an activator of the transcription factors Nrf2 and AP-1 through shared kinase signaling pathways that also purportedly contribute to stellate cell activation. The present study examined the role of oxidative stress in ARE- and TRE-regulated gene induction in isolated hepatic stellate cells. Using a portion of the human Nqo1 promoter consisting of an ARE imbedded TRE, it was demonstrated that while the ARE was responsible for mediating inducible gene expression in response to the electrophiles 4-HNE and tBHQ, the TRE was refractory to induction by either electrophiles or PMA. It was demonstrated that stellate cells possess nuclear TRE-binding proteins that were identified as JunB, JunD, Fra1, and Fra2, which were unaffected by either electrophiles or PMA treatment. This report demonstrates that, in contrast to the ARE, the TRE and its binding cognate AP-1 did not mediate independent gene induction in hepatic stellate cells. This observation is significant given the presumed importance attributed to AP-1 in mediating profibrogenic gene expression.