Celastrol inhibits interleukin-17A-stimulated rheumatoid fibroblast-like synoviocyte migration and invasion through suppression of NF-κB-mediated matrix metalloproteinase-9 expression

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.