科研之友
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摘要
Objectives. Recent studies indicate that the anti-malarial agent artemisinin and its derivatives may exert an anti-inflammatory effect. In this study, we explored the effect of artesunate, an artemisinin derivative, on tumour necrosis factor (TNF)-alpha-induced production of interleukins, IL-1 beta, IL-6 and IL-8, in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and further investigated the signal mechanism by which this compound modulates those cytokines' production. Methods. RA FLS obtained from patients with active RA were stimulated with TNF-alpha and incubated with artesunate, and IL-1 beta, IL-6 and IL-8 production was measured by ELISA. DNA-binding activity and nuclear translocation of nuclear factor kappa B (NF-kappa B) were measured by a sensitive multi-well colourimetric assay and confocal fluorescence microscopy, respectively. Signal transduction proteins expression was measured by western blot. Results. Artesunate decreased the secretion of IL-1 beta, IL-6 and IL-8 from TNF-alpha-stimulated RA FLS in a dose-dependent manner. Artesunate also prevented TNF-alpha-induced nuclear NF-kappa B translocation, DNA-binding activity and gene transcriptional activity, as well as phosphorylation and degradation of I kappa B alpha, but phosphorylation of p38 mitogen-activated protein kinase, extracelluar signal-regulated kinase and c-Jun N-terminal kinase were unaffected. The production of IL-1 beta, IL-6 and IL-8 induced by TNF-alpha was decreased by pyrrolidine dithiocarbamate (PDTC), a chemical inhibitor of NF-kappa B. These observations suggest that artesunate inhibits production of IL-1 beta, IL-6 and IL-8 through inhibition of NF-kappa B signalling pathway. We also showed that artesunate prevented Akt phosphorylation. TNF-a-induced production of IL-1 beta, IL-6 and IL-8 was hampered by treatment with the phosphatidylinositol 3 (P13) kinase inhibitor LY294002, suggesting that inhibition of Akt activation might inhibit IL-1 beta, IL-6 and IL-8 production induced by TNF-alpha. Conclusions. Our results indicate that artesunate exerts an anti-inflammatory effect in RA FLS and provide the evidence that artesunate may have therapeutic potential for RA.
