Wung B S, Hsu M C, Wu C C, Hsieh C W
Department of Applied Microbiology, National Chiayi University, Chiayi, Taiwan.
Life Sci. 2005 Dec 12;78(4):389-97. doi: 10.1016/j.lfs.2005.04.052. Epub 2005 Sep 16.
Resveratrol, a polyphenolic phytoaxelin present in red wine, has been suggested to protect against atherosclerosis and cardiovascular disease because of its antioxidant effects. Intercellular adhesion molecule (ICAM-1), induced by cytokines, has been hypothesized to play a role in the early events during atherosclerosis. In this study we tested the effects of resveratrol upon both IL-6-induced ICAM-1 gene expression and its underlying signaling pathways in endothelial cells (ECs). Resveratrol was found to inhibit both TNFalpha- and IL-6-induced ICAM-1 gene expression at the promoter, transcriptional and protein levels. Resveratrol also abrogates the tyr705 phosphorylation of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner. Although quercetin had similar effects, resveratrol showed higher inhibitory properties following 2-4 h pretreatments. Resveratrol has been shown to induce the activity of endothelial nitric oxide synthase (eNOS) and increase NO production. Consistent with this, the treatment of ECs with a NO donor (SNAP) reduces IL-6-induced STAT3 phosphorylation. Conversely, exposure of ECs to a NOS inhibitor reversed the effects of resveratrol upon IL-6-induced STAT3 phosphorylation. Furthermore, ECs transfected with constitutively active Rac1 (RacV12) showed increases in ICAM-1 promoter activity, intracellular reactive oxygen species (ROS) levels and STAT3 phosphorylation, and these increases were attenuated by resveratrol treatment. In summary, we demonstrate for the first time that resveratrol inhibits IL-6-induced ICAM-1 gene expression, in part, by interfering with Rac-mediated pathways via the attenuation of STAT3 phosphorylation. This study therefore provides important new insights that may contribute to the proposed beneficial effects of resveratrol in endothelial responses to cytokines during inflammation.
白藜芦醇是一种存在于红酒中的多酚类植物抗毒素，因其抗氧化作用，被认为可以预防动脉粥样硬化和心血管疾病。细胞间黏附分子（ICAM-1）由细胞因子诱导产生，据推测在动脉粥样硬化早期事件中发挥作用。在本研究中，我们测试了白藜芦醇对白细胞介素-6（IL-6）诱导的ICAM-1基因表达及其在内皮细胞（ECs）中的潜在信号通路的影响。研究发现，白藜芦醇在启动子、转录和蛋白质水平上均抑制肿瘤坏死因子α（TNFα）和IL-6诱导的ICAM-1基因表达。白藜芦醇还以剂量和时间依赖性方式消除IL-6处理的ECs中信号转导和转录激活因子3（STAT3）的酪氨酸705磷酸化。虽然槲皮素具有类似的作用，但在预处理2-4小时后，白藜芦醇显示出更高的抑制特性。白藜芦醇已被证明可诱导内皮型一氧化氮合酶（eNOS）的活性并增加一氧化氮（NO）的产生。与此一致的是，用NO供体（硝普钠，SNAP）处理ECs可降低IL-6诱导的STAT3磷酸化。相反，将ECs暴露于一氧化氮合酶抑制剂可逆转白藜芦醇对IL-6诱导的STAT3磷酸化的影响。此外，用组成型活性Rac1（RacV12）转染的ECs显示ICAM-1启动子活性、细胞内活性氧（ROS）水平和STAT3磷酸化增加，而白藜芦醇处理可减弱这些增加。总之，我们首次证明白藜芦醇部分通过减弱STAT3磷酸化来干扰Rac介导的信号通路，从而抑制IL-6诱导的ICAM-1基因表达。因此，本研究提供了重要的新见解，可能有助于解释白藜芦醇在炎症过程中对内皮细胞对细胞因子反应的有益作用。
