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Int Immunopharmacol. 2012 Dec;14(4):422-31. doi: 10.1016/j.intimp.2012.08.016. Epub 2012 Sep 3.

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

Author information

1
Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou 225000, China.

Abstract

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.

PMID:
22954486
DOI:
10.1016/j.intimp.2012.08.016
[Indexed for MEDLINE]

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