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Triptolide, an active compound identified in a traditional Chinese herb, induces apoptosis of rheumatoid synovial fibroblasts
Arthritis Res Ther volume 5, Article number: 146 (2003)
Extracts of Tripterygium wilfordii Hook F (TWHF), a traditional Chinese herb, have been reported to show efficacy in patients with rheumatoid arthritis (RA). It was also reported that TWHF extracts suppress inflammation in animal models of RA, and inhibit the production of proinflammatory cytokines by several kinds of cells in vitro.
Since RA is not only characterized by inflammation, but also by synovial proliferation in the joints, we examined whether triptolide (a constituent of TWHF) could influence the proliferation of rheumatoid synovial fibroblasts (RSF) by induction of apoptosis.
RSF were obtained from RA patients during surgery and were treated with triptolide or other disease-modifying antirheumatic drugs under various conditions. The viability and proliferation of RSF were measured by the 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate assay and by 5-bromo-2'-deoxyuridine incorporation, respectively. Apoptosis was identified by detection of DNA fragmentation using an ELISA and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. The role of caspases in apoptosis of RSF was analyzed by measuring caspase-3 activity, and we also studied DNA fragmentation with or without caspase inhibitors. Activation of the peroxisome proliferator-activated receptor gamma (PPARγ) was assessed by a luciferase reporter gene assay using RSF transfected with a plasmid containing the peroxisome proliferator response element.
Triptolide decreased viability, inhibited proliferation, and induced apoptosis of RSF in a concentration-dependent manner at very low (nanomolar) concentrations, whereas bucillamine, D-penicil-lamine and methotrexate did not affect cell proliferation at all. Although PPARã activation was induced by 15-deoxy-Δ12,14-prostaglandin J2, triptolide did not induce it under the same experimental conditions. Caspase-3 activity was increased by treatment with triptolide and was suppressed by a pan-caspase inhibitor. Triptolide-induced DNA fragmentation was inhibited by inhibitors of caspase-3, caspase-8 and caspase-9.
Although the mechanism of action remains to be studied, triptolide may possibly have a disease-modifying effect in patients with RA.
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government.
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Kusunoki, N., Yamazaki, R. & Kawai, S. Triptolide, an active compound identified in a traditional Chinese herb, induces apoptosis of rheumatoid synovial fibroblasts. Arthritis Res Ther 5, 146 (2003) doi:10.1186/ar947
- Rheumatoid Arthritis
- Luciferase Reporter Gene Assay
- Tripterygium Wilfordii