Rheumatology Advance Access originally published online on February 21, 2007
Rheumatology 2007 46(6):920-926; doi:10.1093/rheumatology/kem014
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Anti-malarial agent artesunate inhibits TNF-
-induced production of proinflammatory cytokines via inhibition of NF-
B and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes
Department of Rheumatology and 1Department of Nephrology, The First Affiliated Hospital, SUN Yat-sen University, Guangzhou, Guangdong, PR China and 2Department of Pathology, School of Medicine, Northwestern University, Chicago, IL, USA
Correspondence to: H. Xu, MD, PhD, Department of Rheumatology, The First Affiliated Hospital, SUN Yat-sen University, NO 58 Zhongshan Road 2, Guangzhou, Guangdong 510080, PR China. E-mail: xuhanshi{at}hotmail.com; xuhanshi{at}mail.sysu.edu.cn
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Abstract |
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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)-
-induced production of interleukins, IL-1ß, 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- and incubated with artesunate, and IL-1ß, IL-6 and IL-8 production was measured by ELISA. DNA-binding activity and nuclear translocation of nuclear factor kappa B (NF-
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-1ß, IL-6 and IL-8 from TNF--stimulated RA FLS in a dose-dependent manner. Artesunate also prevented TNF--induced nuclear NF-B translocation, DNA-binding activity and gene transcriptional activity, as well as phosphorylation and degradation of IB, but phosphorylation of p38 mitogen-activated protein kinase, extracelluar signal-regulated kinase and c-Jun N-terminal kinase were unaffected. The production of IL-1ß, IL-6 and IL-8 induced by TNF- was decreased by pyrrolidine dithiocarbamate (PDTC), a chemical inhibitor of NF-B. These observations suggest that artesunate inhibits production of IL-1ß, IL-6 and IL-8 through inhibition of NF-B signalling pathway. We also showed that artesunate prevented Akt phosphorylation. TNF--induced production of IL-1ß, IL-6 and IL-8 was hampered by treatment with the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, suggesting that inhibition of Akt activation might inhibit IL-1ß, IL-6 and IL-8 production induced by TNF-.
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.
KEY WORDS: Artesunate, Cytokines, Rheumatoid arthritis, Signal transduction, Fibroblast-like synoviocytes
Submitted 11 September 2006;
revised version accepted 5 January 2007.
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