Byun H S, Song J K, Kim Y-R, Piao L, Won M, Park K A, Choi B L, Lee H, Hong J H, Park J, Seok J H, Lee Y J, Kang S W, Hur G M
Department of Pharmacology, Infection Signaling Network Research Center, Research Institute for Medical Sciences, Daejeon, Korea.
Rheumatology (Oxford). 2008 Mar;47(3):301-8. doi: 10.1093/rheumatology/kem368.
Resveratrol is a naturally occurring polyphenol, which possesses chemotherapeutic potential through its ability to trigger apoptosis. The objective of this study was to investigate the major determinant for the apoptotic cell death induction by resveratrol in fibroblast-like synoviocytes (FLS) derived from patients with RA.
The effect of resveratrol on apoptotic cell death was quantified in a population of subG1 in RA FLS by flow cytometry. The underlying signalling mechanism for apoptotic death was examined by analysing mitochondrial membrane potential, activation of the caspase cascade and translocation of Bid.
We show that activation of caspase-8 is essential for triggering resveratrol-induced apoptotic signalling via the involvement of the mitochondrial pathway in RA FLS. Our findings also suggest that this enhanced apoptosis caused by resveratrol occurred in RA FLS irrespective of p53 status. Exposure to resveratrol caused extensive apoptotic cell death, along with a caspase-dependent (activation of caspase-9 and -3, poly ADPribose polymerase (PARP) cleavage and mitochondrial cytochrome c release) or caspase-independent [translocation of apoptosis-inducing factor (AIF) to the nucleus] signalling pathway. Analysis of upstream signalling events affected by resveratrol revealed that the activated caspase-8 triggered mitochondrial apoptotic events by inducing Bid cleavage without any alteration in the levels of Bax, Bcl-xL or Bcl2. The caspase-8 inhibitor or over-expression of crmA abrogated cell death induced by resveratrol and prevented processing of the downstream cascade.
The results suggest that resveratrol causes activation of caspase-8, which in turn results in modulation of mitochondrial apoptotic machinery to promote apoptosis of RA FLS.
白藜芦醇是一种天然存在的多酚，具有通过触发细胞凋亡发挥化疗作用的潜力。本研究的目的是探究白藜芦醇诱导类风湿关节炎（RA）患者来源的成纤维样滑膜细胞（FLS）凋亡性细胞死亡的主要决定因素。
采用流式细胞术对RA FLS中G1期亚群细胞的白藜芦醇诱导凋亡性细胞死亡作用进行定量分析。通过分析线粒体膜电位、半胱天冬酶级联反应的激活以及Bid的转位，研究凋亡性死亡的潜在信号传导机制。
我们发现，在RA FLS中，半胱天冬酶-8的激活对于通过线粒体途径触发白藜芦醇诱导的凋亡信号至关重要。我们的研究结果还表明，无论p53状态如何，白藜芦醇在RA FLS中均可引起这种增强的细胞凋亡。白藜芦醇暴露导致广泛的凋亡性细胞死亡，同时伴有半胱天冬酶依赖性（半胱天冬酶-9和-3的激活、聚ADP核糖聚合酶（PARP）的裂解以及线粒体细胞色素c的释放）或半胱天冬酶非依赖性[凋亡诱导因子（AIF）转位至细胞核]信号通路。对白藜芦醇影响的上游信号事件进行分析发现，激活的半胱天冬酶-8通过诱导Bid裂解触发线粒体凋亡事件，而Bax、Bcl-xL或Bcl2的水平未发生任何改变。半胱天冬酶-8抑制剂或crmA的过表达可消除白藜芦醇诱导的细胞死亡，并阻止下游级联反应的进行。
结果表明白藜芦醇可导致半胱天冬酶-8激活，进而调节线粒体凋亡机制，促进RA FLS凋亡。
