Celastrol inhibits interleukin-17A-stimulated rheumatoid fibroblast-like synoviocyte migration and invasion through suppression of NF-κB-mediated matrix metalloproteinase-9 expression
Celastrol inhibits interleukin-17A-stimulated rheumatoid fibroblast-like synoviocyte migration and invasion through suppression of NF-κB-mediated matrix metalloproteinase-9 expression
复制标题
DOI：
10.1016/j.intimp.2012.08.016
复制
发表时间：
2012-12-01
影响因子：
5.6
通讯作者：
Liu, Yan-qing
中科院分区：
文献类型：
--
作者：
Li, Guo-qing;Zhang, Yu;Liu, Yan-qing
白介素17A(IL-17A)诱导的成纤维细胞样滑膜细胞的迁移和侵袭在类风湿关节炎(RA)的发病机制中起重要作用。尽管引入了新的生物制剂，但超过30%的RA患者对现有的治疗方法具有抵抗力。因此，有必要开发新的抗关节炎药物。最近的研究表明，雷公藤红素在佐剂性关节炎(AIA)模型中具有抗关节炎活性。然而，雷公藤红素对RA-FLSS迁移和侵袭的影响及其分子机制尚不清楚。结果表明，雷公藤红素可抑制IL-17A诱导的RA-FLSS细胞的迁移和侵袭能力。此外，雷公藤红素还可抑制IL-17A诱导的RA-FL中基质金属蛋白酶-9(MMP9)的表达和蛋白表达，以及MMP9的蛋白分解活性。此外，雷公藤红素通过抑制核因子-kappaB(NF-kappa B)在启动子上的结合活性抑制了MMP9的转录活性，并抑制了IkappaBα的磷酸化和核转位。结论：雷公藤红素可能通过抑制核因子kappaB介导的MMP9的表达而抑制IL-17A诱导的迁移和侵袭。这些结果为进一步测试和验证雷公藤红素作为治疗人类类风湿性关节炎的常规药物的辅助药物提供了强有力的理由。(C)2012爱思唯尔B.V.保留所有权利。
Interleukin-17A (IL-17A)-induced migration and invasion of fibroblast-like synoviocytes (FLSs) is critical for the pathogenesis of rheumatoid arthritis (RA). More than 30% of RA patients are resistant to available therapies, despite the introduction of novel biologic agents. Therefore, it is necessary to develop new anti-arthritic agents. Recent studies have demonstrated that celastrol has anti-arthritic activity in an adjuvant-induced arthritis (AIA) model. However, the effect and molecular mechanisms of celastrol on the migration and invasion of RA-FLSs are not yet understood. Results showed that treatment of RA-FLSs with celastrol suppressed the IL-17A-induced migration and invasion abilities of the cells. In addition, celastrol inhibited IL-17A-induced matrix metalloproteinase (MMP)-9 mRNA and protein expression, and the proteolytic activity of MMP-9 in RA-FLSs. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppression of the binding activity of nuclear factor-kappa B (NF-kappa B) in the MMP-9 promoter, and inhibited I kappa B alpha phosphorylation and nuclear translocation of NF-kappa B. In conclusion, celastrol can inhibit IL-17A-induced migration and invasion by suppressing NF-kappa B-mediated MMP-9 expression in RA-FLSs. These results provide a strong rationale for further testing and validation of celastrol as an adjunct with conventional drugs for the treatment of RA in humans. (c) 2012 Elsevier B.V. All rights reserved.