Lyss G, Knorre A, Schmidt T J, Pahl H L, Merfort I
Institute of Pharmaceutical Biology, Albert-Ludwigs-Universität Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany.
J Biol Chem. 1998 Dec 11;273(50):33508-16. doi: 10.1074/jbc.273.50.33508.
The sesquiterpene lactone helenalin is a potent anti-inflammatory 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-kappaB, a central mediator of the human immune response. These drugs must target a central step in NF-kappaB pathway, since they inhibit NF-kappaB induction by four different stimuli. It has previously been reported that sesquiterpene lactones exert their effect by inhibiting degradation of IkappaB, the inhibitory subunit of NF-kappaB. These data contradicted our report that IkappaB is not detectable in helenalin-treated, ocadaic acid-stimulated cells. Here we use confocal laser scanning microscopy to demonstrate the presence of IkappaB-released, nuclear NF-kappaB in helenalin-treated, tumor necrosis factor-alpha stimulated cells. These data show that neither IkappaB degradation nor NF-kappaB nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-kappaB. This sesquiterpene lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-kappaB.
倍半萜内酯海伦内酯是一种强效抗炎药物，尽管进行了大量研究，但其分子作用机制仍不清楚。我们之前已经表明，海伦内酯和其他倍半萜内酯选择性抑制转录因子NF-κB的激活，NF-κB是人类免疫反应的核心介质。这些药物必须靶向NF-κB通路中的一个核心步骤，因为它们抑制四种不同刺激诱导的NF-κB。之前有报道称，倍半萜内酯通过抑制NF-κB抑制亚基IkappaB的降解发挥作用。这些数据与我们的报告相矛盾，我们的报告显示在经海伦内酯处理、冈田酸刺激的细胞中检测不到IkappaB。在这里，我们使用共聚焦激光扫描显微镜来证明在经海伦内酯处理、肿瘤坏死因子-α刺激的细胞中存在释放IkappaB的核NF-κB。这些数据表明，海伦内酯既不抑制IkappaB的降解，也不抑制NF-κB的核转位。相反，我们提供证据表明海伦内酯选择性地使NF-κB的p65亚基烷基化。这种倍半萜内酯是第一种被证明通过直接修饰NF-κB发挥作用的抗炎剂。
