Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-κB-mediated matrix metalloproteinase-9 expression

Guoqing Li; Dan Liu; Yu Zhang; Yayun Qian; Hua Zhang; Shiyu Guo; Masataka Sunagawa; Tadashi Hisamitsu; Yanqing Liu

doi:10.1371/journal.pone.0068905

Celastrol inhibits lipopolysaccharide-stimulated rheumatoid fibroblast-like synoviocyte invasion through suppression of TLR4/NF-κB-mediated matrix metalloproteinase-9 expression

PLoS One. 2013 Jul 4;8(7):e68905. doi: 10.1371/journal.pone.0068905. Print 2013.

Authors

Guoqing Li¹, Dan Liu, Yu Zhang, Yayun Qian, Hua Zhang, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Yanqing Liu

Affiliation

¹ Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy*
Arthritis, Experimental / genetics
Arthritis, Experimental / pathology
Arthritis, Rheumatoid / drug therapy
Arthritis, Rheumatoid / genetics
Arthritis, Rheumatoid / pathology
Cell Cycle / drug effects
Cell Movement / drug effects
Cell Survival / drug effects
Collagen Type II
Female
Gene Expression Regulation / drug effects*
Humans
Joint Capsule / drug effects*
Joint Capsule / metabolism
Joint Capsule / pathology
Lipopolysaccharides / pharmacology
Matrix Metalloproteinase 9 / genetics
Matrix Metalloproteinase 9 / metabolism
NF-kappa B / antagonists & inhibitors
NF-kappa B / genetics
NF-kappa B / metabolism
Pentacyclic Triterpenes
Primary Cell Culture
Rats
Rats, Wistar
Signal Transduction
Toll-Like Receptor 4 / antagonists & inhibitors
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism
Triterpenes / pharmacology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Collagen Type II
Lipopolysaccharides
NF-kappa B
Pentacyclic Triterpenes
Tlr4 protein, rat
Toll-Like Receptor 4
Triterpenes
Matrix Metalloproteinase 9
celastrol

Grants and funding

This study was supported by grants from National Natural Science Foundation of China (no. 81173603), and Postgraduate Research and Innovation Project of Jiangsu Province (no. CXZZ11-0998). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.