Abstract
BackgroundInvasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of nuclear factor-kappa B (NF-κB) pathway play a critical role in RA-FLS invasion induced by interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α). The present study aimed to explore the anti-invasive activity and mechanism of Celastrus orbiculatus extract (COE) on IL-1β and TNF-α combination-stimulated human RA-FLSs.MethodsWe investigated the effect of COE on IL-1β and TNF-α combination-induced FLS invasion as well as MMP expression and explored upstream signal transduction.ResultsCOE suppressed IL-1β and TNF-α combination-stimulated FLSs invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that COE inhibited the transcriptional activity of MMP-9 by suppression of the binding activity of NF-κB in the MMP-9 promoter, and inhibited IκBα phosphorylation and nuclear translocation of NF-κB.ConclusionsCOE inhibits IL-1β and TNF-α combination-induced FLSs invasion by suppressing NF-κB-mediated MMP-9 expression.
Highlights
Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA)
Growing evidence suggests that fibroblast-like synoviocytes (FLSs) in the lining layer can attach to the cartilage and invade the extracellular matrix
Effect of Celastrus orbiculatus extract (COE) on IL-1β and TNF-α-induced FLSs migration and invasion As shown in Figure 1(A), this experiment was undertaken to examine the cytotoxic effect of COE on human RA-FLSs
Summary
Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). Growing evidence suggests that fibroblast-like synoviocytes (FLSs) in the lining layer can attach to the cartilage and invade the extracellular matrix. This aggressive invasive behaviour has an important role in initiating and driving RA [3,4]. It is well established that pro-inflammatory cytokines are key mediators of RA-FLS invasion and are involved in the pathogenesis of RA [3] Cytokines, such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor (TNFα), can stimulate RA-FLS invasion, and increase the production of matrix metalloproteinases (MMPs), which, in turn, aggravate synovial inflammation resulting in joint destruction [7,8,9,10,11]. MMP-2 and MMP-9, called collagenases, degrade type IV collagen, gelatin and elastin, and are induced in RA-FLS by pro-inflammatory cytokines, through the activation of transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) [15]
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