Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou 225000, China.
Int Immunopharmacol. 2012 Dec;14(4):422-31. doi: 10.1016/j.intimp.2012.08.016. Epub 2012 Sep 3.
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-κB (NF-κB) in the MMP-9 promoter, and inhibited IκBα phosphorylation and nuclear translocation of NF-κB. In conclusion, celastrol can inhibit IL-17A-induced migration and invasion by suppressing NF-κB-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.
白细胞介素-17A（IL-17A）诱导成纤维样滑膜细胞（FLSs）的迁移和侵袭对于类风湿关节炎（RA）的发病机制至关重要。尽管新型生物制剂的出现，仍有超过 30%的 RA 患者对现有疗法产生耐药。因此，有必要开发新的抗关节炎药物。最近的研究表明，雷公藤红素在佐剂诱导关节炎（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，雷公藤红素处理 RA-FLSs 可抑制细胞的 IL-17A 诱导的迁移和侵袭能力。此外，雷公藤红素抑制了 IL-17A 诱导的 RA-FLSs 中基质金属蛋白酶（MMP）-9 mRNA 和蛋白表达，以及 MMP-9 的蛋白水解活性。此外，我们的结果表明，雷公藤红素通过抑制 MMP-9 启动子中核因子-κB（NF-κB）的结合活性，抑制 IκBα 磷酸化和 NF-κB 的核转位，从而抑制 MMP-9 的转录活性。总之，雷公藤红素通过抑制 NF-κB 介导的 MMP-9 表达，可抑制 IL-17A 诱导的 RA-FLSs 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辅助药物与传统药物联合治疗人类 RA 提供了有力依据。
