title: Celastrol inhibits interleukin-17A-stimulated rheumatoid fibroblast-like synoviocyte migration and invasion through suppression of NF-κB-mediated matrix metalloproteinase-9 expression.
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.
authors.affiliation: Department of Rheumatology, Clinical Medical College, Yangzhou University, Yangzhou 225000, China.
authors.forename: Guo-qing
authors.initials: GQ
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Ya-yun
authors.initials: YY
authors.lastname: Qian
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Shi-yu
authors.initials: SY
authors.lastname: Guo
authors.forename: Masataka
authors.initials: M
authors.lastname: Sunagawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hisamitsu
authors.forename: Yan-qing
authors.initials: YQ
authors.lastname: Liu
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020381:Interleukin-17; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D059370:RNA Folding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013582:Synovial Fluid / Q000166:cytology*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020381:Interleukin-17; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D014315:Triterpenes; D020780:Matrix Metalloproteinase 9; C050414:celastrol