Cordycepin inhibits IL-1β-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts
Cordycepin inhibits IL-1β-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts
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DOI：
10.1093/rheumatology/ken417
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发表时间：
2009-01-01
期刊：
影响因子：
5.5
通讯作者：
Lee, Y. -R.
中科院分区：
文献类型：
--
作者：
Noh, E. -M.;Kim, J. -S.;Lee, Y. -R.
Objective. MMP是细胞外基质降解的关键酶，其表达在炎症性疾病中起重要作用。虫草素（Cordycepin，3 '-deoxyadenosine）是蛹虫草（Cordyceps militaris）中的一种生物活性成分，具有抗癌、抗炎、抗感染等多种药理活性。本研究以RA滑膜成纤维细胞（RA synovial fibroblasts，RASFs）为研究对象，探讨虫草素对IL-1 β诱导的MMP-1和MMP-3表达的抑制作用及其分子基础。从12例RA患者的滑膜组织中分离RASFs，并进行单层培养。采用Western blotting和real-time PCR检测MMP-1和MMP-3的表达。通过ELISA分析趋化因子。蛋白质印迹法检测丝裂原活化蛋白激酶的磷酸化水平。电泳迁移率改变法检测DNA与核因子-κ B（NF-κ B）和激活蛋白-1（AP-1）的结合活性。虫草素以剂量依赖方式抑制IL-1 β诱导的RASFs MMP-1和MMP-3的表达。在各种趋化因子[如单核细胞趋化蛋白-1（MCP-1）、GRO-α、活化后调节、正常T细胞表达和推测分泌（RANTES）和上皮中性粒细胞活化肽78（ENA-78）]中，虫草素特异性阻断RASF中IL-1 β诱导的ENA-78产生。此外，虫草素显著抑制IL-1 β诱导的p38/JNK和AP-1活化，但不抑制细胞外信号调节激酶（ERK）和NF-κ B活化。虫草素是IL-1 β诱导的趋化因子产生和MMP表达的有效抑制剂，并强烈阻断RASF中的p38/JNK/AP-1信号通路。
Objective. MMP is a key enzyme in the degradation of extracellular matrices, and its expression plays important roles in inflammatory diseases. Cordycepin (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological activities, such as anti-cancer, anti-inflammatory and anti-infection activities. In this study, we aimed at the inhibitory effect of cordycepin on IL-1 beta-induced MMP-1 and MMP-3 expression as well as the molecular basis using RA synovial fibroblasts (RASFs).Methods. RASFs were isolated from synovial tissue obtained from 12 patients with RA and cultured in monolayer. Expression of MMP-1 and MMP-3 was evaluated using western blotting and real-time PCR. Chemokines were analysed by ELISA. The phosphorylation of mitogen-activated protein kinase was measured by western blotting. Electrophoretic mobility shift assay was performed to evaluate binding activities of DNA to nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1).Results. Cordycepin inhibited IL-1 beta-induced MMP-1 and MMP-3 expressions in RASFs in a dose-dependent manner. Among various chemokines [such as monocyte chemoattractant protein-1 (MCP-1), GRO-alpha, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) and epithelial neutrophil activating peptide 78 (ENA-78)], cordycepin specifically blocked IL-1 beta-induced ENA-78 production in RASF. Moreover, cordycepin significantly inhibited IL-1 beta-induced p38/JNK and AP-1 activation, but not extracellular signal-regulated kinase (ERK) and NF-kappa B activation.Conclusions. Cordycepin is a potent inhibitor of IL-1 beta-induced chemokine production and MMP expression and strongly blocks the p38/JNK/AP-1 signalling pathway in RASFs.