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The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte.
- Source :
-
Rheumatology international [Rheumatol Int] 2011 Jan; Vol. 31 (1), pp. 53-60. Date of Electronic Publication: 2009 Oct 27. - Publication Year :
- 2011
-
Abstract
- Increasing evidence indicates that the anti-malarial agent artemisinin and its derivatives may exert anti-angiogenic effect. In the present study, we explored the effect of artesunate, a artemisinin derivative, on TNFα- and hypoxia-induced expression of hypoxia inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) and inteleukin-8 (IL-8) in human rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), and further investigated the signal mechanism by which this compound modulates HIF-1α, VEGF and IL-8 expression. RA FLS obtained from patients with active rheumatoid arthritis were pretreated with artesunate, and then stimulated with TNFα and hypoxia. Production of VEGF and IL-8 was measured by ELISA. Nuclear location of HIF-1α was measured by confocal fluorescence microscopy. HIF-1α and other signal transduction proteins expression was measured by Western blot. Artesunate decreased the secretion of VEGF and IL-8 from TNFα- or hypoxia-stimulated RA FLS in a dose-dependent manner. Artesunate also inhibited TNFα- or hypoxia-induced nuclear expression and translocation of HIF-1α. We also showed that artesunate prevented Akt phosphorylation, but did not find evidence that phosphorylation of p38 and ERK was affected. TNFα- or hypoxia-induced secretion of VEGF and IL-8 and expression of HIF-1α were hampered by treatment with the PI3 kinase inhibitor LY294002, suggesting that inhibition of PI3 kinase/Akt activation might inhibit VEGF and IL-8 secretion and HIF-1α expression induced by TNFα or hypoxia. Our results suggest that artesunate inhibits angiogenic factor expression in RA FLS, and provide novel evidence that, as a low-cost agent, artesunate may have therapeutic potential for RA.
- Subjects :
- Adult
Artesunate
Blotting, Western
Cells, Cultured
Extracellular Signal-Regulated MAP Kinases metabolism
Female
Flow Cytometry
Humans
Interleukin-8 metabolism
Middle Aged
Phosphorylation drug effects
Signal Transduction drug effects
Signal Transduction physiology
Statistics, Nonparametric
Synovial Membrane cytology
Synovial Membrane metabolism
Antimalarials pharmacology
Artemisinins pharmacology
Arthritis, Rheumatoid metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Synovial Membrane drug effects
Vascular Endothelial Growth Factor A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1437-160X
- Volume :
- 31
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Rheumatology international
- Publication Type :
- Academic Journal
- Accession number :
- 19859713
- Full Text :
- https://doi.org/10.1007/s00296-009-1218-7