Kojima Ryoji, Kawachi Masanao, Ito Mikio
Laboratory of Analytical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
Laboratory of Analytical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
Int Immunopharmacol. 2015 Feb;24(2):267-275. doi: 10.1016/j.intimp.2014.12.016. Epub 2014 Dec 19.
Butein (3,4,2',4'-tetrahydroxychalcone), a flavonoid derivative, has been reported to show several biological actions, including anti-inflammatory and anti-cancer. However, the possible molecular mechanisms involved are poorly understood. Treatment of human umbilical vein endothelial cells (HUVECs) with butein significantly inhibited cell surface intercellular adhesion molecule-1 (ICAM-1) expression, ICAM-1 protein synthesis, and mRNA expression induced by tumor necrotic factor-α (TNF-α) and/or phorbol 12-myristate 13-acetate (PMA). Electrophoretic mobility shift assay revealed that butein blocked activation of transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), induced by TNF-α and PMA. Moreover, butein abolished TNF-α- and PMA-induced IκBα phosphorylation, which participates in NF-κB activation, and PMA-induced phosphorylation of c-Jun, a subunit composed of AP-1. In vitro, butein inhibited the phosphorylation of c-Jun, binding to GST beads, mediated by JNK isolated from PMA-treated cells. The inhibitory action of butein on the JNK-mediated in vitro c-Jun phosphorylation was abrogated in the presence of ATP. These results indicate that in HUVECs, butein suppresses the expression of ICAM-1 mRNA and protein through the inhibition of the activation of NF-κB and AP-1 induced by TNF-α and PMA, that the inhibitory action of butein on NF-κB activation results from the inhibition of IκBα phosphorylation by IκB kinase (IKK), and that the inactivation of PMA-activated AP-1 by butein is due to the blocking of JNK-mediated c-Jun phosphorylation through the inhibition of ATP binding.
白杨素（3,4,2',4'-四羟基查耳酮）是一种黄酮类衍生物，据报道具有多种生物学活性，包括抗炎和抗癌作用。然而，其潜在的分子机制尚不清楚。用白杨素处理人脐静脉内皮细胞（HUVECs）可显著抑制肿瘤坏死因子-α（TNF-α）和/或佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的细胞表面细胞间黏附分子-1（ICAM-1）表达、ICAM-1蛋白合成及mRNA表达。电泳迁移率变动分析表明，白杨素可阻断TNF-α和PMA诱导的转录因子核因子-κB（NF-κB）和活化蛋白-1（AP-1）的激活。此外，白杨素可消除TNF-α和PMA诱导的IκBα磷酸化（IκBα磷酸化参与NF-κB激活）以及PMA诱导的c-Jun（AP-1的一个亚基）磷酸化。在体外，白杨素可抑制从PMA处理细胞中分离出的JNK介导的c-Jun与GST珠结合的磷酸化。在ATP存在的情况下，白杨素对JNK介导的体外c-Jun磷酸化的抑制作用被消除。这些结果表明，在HUVECs中，白杨素通过抑制TNF-α和PMA诱导的NF-κB和AP-1激活来抑制ICAM-1 mRNA和蛋白的表达，白杨素对NF-κB激活的抑制作用源于IκB激酶（IKK）对IκBα磷酸化的抑制，白杨素对PMA激活的AP-1的失活是由于通过抑制ATP结合阻断了JNK介导的c-Jun磷酸化。
