Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cells in vitro by blocking NF-κB and ERK signalling
Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cells in vitro by blocking NF-κB and ERK signalling
复制标题
DOI：
10.1038/sj.bjp.0707542
复制
发表时间：
2008-02-01
影响因子：
7.3
通讯作者：
Zheng, S.
中科院分区：
文献类型：
--
作者：
Chen, A.;Zheng, S.
背景和目的：结缔组织生长因子（CTGF）的基因表达在活化的肝星状细胞（HSC）中被诱导，肝星状细胞是肝纤维化的主要效应物，并且细胞外基质（ECM）的产生因此增加。我们以前报道过，姜黄素，咖喱中的黄色色素，抑制ctgf的表达，导致HSC ECM的产生减少。本研究的目的是评价姜黄素抑制HSC中ctgf表达的信号转导途径。实验方法：进行瞬时转染试验以评价信号转导途径激活对ctgf启动子活性的影响。结果：姜黄素对CTGF表达的抑制作用可被NF-κ B激活剂脂多糖（LPS）剂量依赖性逆转。LPS可增加体外培养HSC中CTGF和I型胶原的含量。通过显性活性I κ B激酶（IKK）激活NF-κ B，或通过显性阴性I κ B α抑制NF-κ B，分别引起ctgf启动子活性的刺激或抑制。姜黄素抑制Toll样受体-4的基因表达，导致NF-κ B B的抑制。另一方面，通过抑制剂或显性负性ERK（如姜黄素）中断ERK信号传导可降低NF-κ B活性和ctgf表达。与此相反，刺激ERK信号的组成性活性ERK防止抑制作用的姜黄素。结论和影响：这些结果表明，中断NF-κ B B和ERK信号的姜黄素的结果在体外激活的HSC中的CTGF表达的抑制。
Background and purpose: Gene expression of connective tissue growth factor (CTGF) is induced in activated hepatic stellate cells (HSC), the major effectors in hepatic fibrosis, and production of extracellular matrix (ECM) is consequently increased. We previously reported that curcumin, the yellow pigment in curry, suppressed ctgf expression, leading to decreased production of ECM by HSC. The purpose of this study is to evaluate signal transduction pathways involved in the curcumin suppression of ctgf expression in HSC.Experimental approaches: Transient transfection assays were performed to evaluate effects of activation of signalling pathways on the ctgf promoter activity. Real-time PCR and Western blotting analyses were conducted to determine expression of genes.Results: Suppression of ctgf expression by curcumin was dose-dependently reversed by lipopolysaccharide (LPS), an NF-kappa B activator. LPS increased the abundance of CTGF and type I collagen in HSC in vitro. Activation of NF-kappa B by dominant active I kappa B kinase (IKK), or inhibition of NF-kappa B by dominant negative I kappa B alpha, caused the stimulation, or suppression of the ctgf promoter activity, respectively. Curcumin suppressed gene expression of Toll-like receptor-4, leading to the inhibition of NF-kappa B. On the other hand, interruption of ERK signalling by inhibitors or dominant negative ERK, like curcumin, reduced NF-kappa B activity and in ctgf expression. In contrast, the stimulation of ERK signalling by constitutively active ERK prevented the inhibitory effects of curcumin.Conclusions and implications: These results demonstrate that the interruption of NF-kappa B and ERK signalling by curcumin results in the suppression of ctgf expression in activated HSC in vitro.