Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-κB-mediated matrix metalloproteinase-9 expression.
Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-κB-mediated matrix metalloproteinase-9 expression.
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DOI：
10.1371/journal.pone.0068905
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Li G;Liu D;Zhang Y;Qian Y;Zhang H;Guo S;Sunagawa M;Hisamitsu T;Liu Y
成纤维细胞样滑膜细胞（FLSs）的侵袭在类风湿关节炎（RA）的发病机制中至关重要。金属蛋白酶（MMPs）和toll样受体4 (TLR4)/核因子-κB （NF-κB）通路激活因子在脂多糖（LPS）诱导的RA-FLS侵袭中起关键作用。本研究旨在探讨雷公藤红素对lps刺激的人RA-FLSs的抗创活性，并阐明其作用机制。我们研究了雷公藤红素对lps诱导的FLS迁移、侵袭及MMP表达的影响，并探讨了其上游信号转导。结果表明，雷公藤红素通过抑制MMP-9的表达和活性来抑制lps刺激的FLS迁移和侵袭。此外，我们的研究结果表明，celastrol通过抑制NF-κB在MMP-9启动子中的结合活性来抑制MMP-9的转录活性，并抑制TLR4/MyD88/NF-κB通路。腹腔注射雷公藤红素（0.5 mg/kg和1 mg/kg，连续3周）可明显减轻关节炎模型大鼠的临床症状、关节滑膜增生和炎症细胞浸润。综上所述，雷公藤红素可能通过抑制TLR4/NF-κ b介导的MMP-9的表达，抑制LPS诱导的FLS迁移和侵袭，为雷公藤红素临床治疗RA提供理论依据。
Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasive activity of celastrol on LPS-stimulated human RA-FLSs, and to elucidate the mechanism involved. We investigated the effect of celastrol on LPS-induced FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that celastrol suppressed LPS-stimulated FLS migration and invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppressing the binding activity of NF-κB in the MMP-9 promoter, and suppressed the TLR4/MyD88/NF-κB pathway. Administration of celastrol (0.5 mg/kg and 1 mg/kg, intraperitoneally) daily for 3 weeks in a collagen-induced arthritis rat model markedly alleviated the clinical signs, synovial hyperplasia and inflammatory cell infiltration of joints. In conclusion, celastrol might inhibit FLS migration and invasion induced by LPS by suppressing TLR4/NF-κB-mediated MMP-9 expression, providing a theoretical foundation for the clinical treatment of RA with celastrol.
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影响因子：
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