The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-κB by directly targeting p65
The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-κB by directly targeting p65
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DOI：
10.1074/jbc.273.50.33508
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发表时间：
1998-12-11
影响因子：
4.8
通讯作者：
Merfort, I
中科院分区：
文献类型：
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作者：
Lyss, G;Knorre, A;Merfort, I
倍半萜内酯海伦娜灵是一种有效的抗肿瘤药物，尽管进行了大量的研究，其分子作用机制仍不清楚。我们以前已经表明，海伦娜灵和其他倍半萜内酯选择性抑制激活的转录因子NF-κ B，一个中央调解人的人体免疫反应。这些药物必须靶向NF-κ B B通路中的中心步骤，因为它们抑制四种不同刺激的NF-κ B诱导。此前有报道称，萜烯内酯通过抑制NF-κ B抑制亚基I kappa B的降解来发挥作用。这些数据与我们的报告相矛盾，即I κ B在海伦娜林处理的ocadaic酸刺激的细胞中检测不到。在这里，我们使用共聚焦激光扫描显微镜，以证明存在的I κ B-释放，核NF-κ B在helenalin处理，肿瘤坏死因子-α刺激的细胞。这些数据表明，I κ B降解和NF-κ B核转位均未被helenalin抑制。相反，我们提供的证据表明，helenalin选择性烷基化NF-κ B B的p65亚基。这种倍半萜内酯是第一种显示通过直接修饰NF-κ B发挥其作用的抗炎剂。
The sesquiterpene lactone helenalin is a potent antiinflammatory drug whose molecular mechanism of action remains unclear despite numerous investigations. We have previously shown that helenalin and other sesquiterpene lactones selectively inhibit activation of the transcription factor NF-kappa B, a central mediator of the human immune response. These drugs must target a central step in NF-kappa B pathway, since they inhibit NF-kappa B induction by four different stimuli. It has previously been reported that sesquiterpene lactones exert their effect by inhibiting degradation of I kappa B, the inhibitory subunit of NF-kappa B. These data contradicted our report that I kappa B is not detectable in helenalin-treated, ocadaic acid-stimulated cells. Here we use confocal laser scanning microscopy to demonstrate the presence of I kappa B-released, nuclear NF-kappa B in helenalin-treated, tumor necrosis factor-alpha stimulated cells. These data show that neither I kappa B degradation nor NF-kappa B nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-kappa B. This sesquiterpene lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-kappa B.