Withaferin A strongly elicits IκB kinase β hyperphosphorylation concomitant with potent inhibition of its kinase activity
Withaferin A strongly elicits IκB kinase β hyperphosphorylation concomitant with potent inhibition of its kinase activity
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DOI：
10.1074/jbc.m606728200
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发表时间：
2007-02-16
影响因子：
4.8
通讯作者：
Haegeman, Guy
中科院分区：
文献类型：
--
作者：
Kaileh, Mary;Vanden Berghe, Wim;Haegeman, Guy
转录因子 NF kappa B 在正常和病理生理免疫反应中发挥着关键作用。因此，NF kappa B和调节其激活的信号通路已成为药物开发计划的主要焦点。 Withania somnifera (WS) 是一种药用植物，在巴勒斯坦被广泛用于治疗各种炎症性疾病。在这项研究中，我们表明，WS 的叶子提取物及其主要成分醉茄素 A (WA) 通过硫烷基化敏感的氧化还原机制阻止肿瘤坏死因子诱导的 I kappa B 激酶 beta 激活，从而有效抑制 NF kappa B 激活，而其他 WS 衍生的甾体内酯，如醉茄内酯 A 和 12-脱氧黄芪内酯的效果要差得多。据我们所知，这是植物源性抑制剂对 I kappa B 激酶 β 抑制的首次通讯，与 MEK1/ERK 依赖性 Ser-181 过度磷酸化同时发生。这可以防止 I kappa B 磷酸化和降解，从而阻止 NF kappa B 易位、NF kappa B/DNA 结合和基因转录。综上所述，我们的结果表明，纯 WA 或富含 WA 的 WS 提取物可被视为一类新型 NF kappa B 抑制剂，有望作为新型抗炎剂用于治疗各种炎症性疾病和/或癌症。
The transcription factor NF kappa B plays a critical role in normal and pathophysiological immune responses. Therefore, NF kappa B and the signaling pathways that regulate its activation have become a major focus of drug development programs. Withania somnifera (WS) is a medicinal plant that is widely used in Palestine for the treatment of various inflammatory disorders. In this study we show that the leave extract of WS, as well as its major constituent withaferin A (WA), potently inhibits NF kappa B activation by preventing the tumor necrosis factor-induced activation of I kappa B kinase beta via a thicialkylation-sensitive redox mechanism, whereas other WS-derived steroidal lactones, such as withanolide A and 12-deoxywithastramonolide, are far less effective. To our knowledge, this is the first communication of I kappa B kinase beta inhibition by a plant-derived inhibitor, coinciding with MEK1/ERK-dependent Ser-181 hyperphosphorylation. This prevents I kappa B phosphorylation and degradation, which subsequently blocks NF kappa B translocation, NF kappa B/DNA binding, and gene transcription. Taken together, our results indicate that pure WA or WA-enriched WS extracts can be considered as a novel class of NF kappa B inhibitors, which hold promise as novel anti-inflammatory agents for treatment of various inflammatory disorders and/or cancer.