College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
J Nutr Biochem. 2011 Oct;22(10):902-9. doi: 10.1016/j.jnutbio.2010.07.012. Epub 2010 Dec 28.
Resveratrol (trans-3,4',5-trihydroxystilbene) is one of nonflavonoid polyphenolic phytoalexins found in various plant species, a number of which are components of human diet including grapes and red wines. Resveratrol has exerted several beneficial effects with anti-inflammation, cardioprotection and cancer chemoprevention. However, its mechanisms of action are not completely understood. In this study, we investigated effects of resveratrol on inflammatory gene expression in interferon (IFN)-γ alone-stimulated macrophages and proposed a molecular basis underlying the action. Resveratrol inhibited IFN-γ-induced production of nitric oxide (NO), IFN-γ-inducible protein-10 (IP-10), or the monokine induced by IFN-γ (MIG) in RAW 264.7 macrophages and also that of NO in primary macrophages derived from bone marrows of C3H/HeJ (toll-like receptor-4(-/-)) mice. Moreover, resveratrol diminished IFN-γ-induced protein levels of inducible NO synthase (iNOS), attenuated mRNA levels of iNOS, IP-10 or MIG as well as inhibited IFN-γ-induced promoter activity of iNOS gene, indicating that the phytoalexin could down-regulate inflammatory genes at the transcription level. To understand a mechanism of the action, we tested resveratrol could affect the signal transducers and activation of transcription-1 (STAT-1), a pivotal transcription factor in IFN-γ-induced expression of inflammatory genes. Resveratrol inhibited IFN-γ-induced transcriptional activity of STAT-1 in macrophages and also IFN-γ-induced Tyr(701) or Ser(727) phosphorylation of STAT-1. We then focused on protein kinases upstream STAT-1 phosphorylation. Resveratrol inhibited IFN-γ-induced activation of Janus kinase-2 (JAK-2) and also the extracellular signal-regulated kinase, in which JAK-2 was more sensitive. Taken together, this study proposes a new mechanism of resveratrol, blocking JAK/STAT-1 pathway that controls inflammatory responses in IFN-γ-activated macrophages.
白藜芦醇（反式-3,4',5-三羟基二苯乙烯）是在各种植物物种中发现的非类黄酮多酚植物抗毒素之一，其中一些是人类饮食的组成部分，包括葡萄和红酒。白藜芦醇具有抗炎、心脏保护和癌症化学预防等多种有益作用。然而，其作用机制尚不完全清楚。在这项研究中，我们研究了白藜芦醇对干扰素（IFN）-γ单独刺激的巨噬细胞中炎症基因表达的影响，并提出了其作用的分子基础。白藜芦醇抑制 IFN-γ诱导的 RAW 264.7 巨噬细胞中一氧化氮（NO）、IFN-γ诱导蛋白-10（IP-10）或 IFN-γ诱导的单核细胞趋化因子（MIG）的产生，也抑制 C3H/HeJ（Toll 样受体-4(-/-)）小鼠骨髓来源的原代巨噬细胞中 NO 的产生。此外，白藜芦醇降低 IFN-γ诱导的诱导型一氧化氮合酶（iNOS）蛋白水平，减弱 iNOS、IP-10 或 MIG 的 mRNA 水平，并抑制 IFN-γ诱导的 iNOS 基因启动子活性，表明该植物抗毒素可在转录水平下调炎症基因。为了了解作用机制，我们测试了白藜芦醇是否可以影响信号转导和转录激活因子-1（STAT-1），这是 IFN-γ诱导炎症基因表达的关键转录因子。白藜芦醇抑制巨噬细胞中 IFN-γ诱导的 STAT-1 转录活性，也抑制 IFN-γ诱导的 STAT-1 Tyr（701）或 Ser（727）磷酸化。然后，我们将重点放在 STAT-1 磷酸化的上游蛋白激酶上。白藜芦醇抑制 IFN-γ诱导的 Janus 激酶-2（JAK-2）和细胞外信号调节激酶的激活，其中 JAK-2 更为敏感。综上所述，本研究提出了白藜芦醇的一种新机制，即阻断 JAK/STAT-1 通路，控制 IFN-γ 激活的巨噬细胞中的炎症反应。
