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EXTENDED REPORT |
1 Centre of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Switzerland
2 Schulthess Clinic, Zurich, Switzerland
3 Institute for Pathology Basle, University Hospital Basle, Switzerland
Correspondence to:
Correspondence to:
Dr M Neidhart
Centre of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH 8091 Zurich, Switzerland; Michel.Neidhart{at}usz.ch
Background: Histone acetylation/deacetylation has a critical role in the regulation of transcription by altering the chromatin structure.
Objective: To analyse the effect of trichostatin A (TSA), a streptomyces metabolite which specifically inhibits mammalian histone deacetylases, on TRAIL-induced apoptosis of rheumatoid arthritis synovial fibroblasts (RASF).
Methods: Apoptotic cells were detected after co-treatment of RASF with TRAIL (200 ng/ml) and TSA (0.5, 1, and 2 µmol/l) by flow cytometry using propidium iodide/annexin-V-FITC staining. Cell proliferation was assessed using the MTS proliferation test. Induction of the cell cycle inhibitor p21Waf/Cip1 by TSA was analysed by western blot. Expression of the TRAIL receptor-2 (DR5) on the cell surface of RASF was analysed by flow cytometry. Levels of soluble TRAIL were measured in synovial fluid of patients with RA and osteoarthritis (OA) by ELISA.
Results: Co-treatment of the cells with TSA and TRAIL induced cell death in a synergistic and dose dependent manner, whereas TRAIL and TSA alone had no effect or only a modest effect. RASF express DR5 (TRAIL receptor 2), but treatment of the cells with TSA for 24 hours did not change the expression level of DR5, as it is shown for cancer cells. TSA induced cell cycle arrest in RASF through up regulation of p21Waf1/Cip1. Levels of soluble TRAIL were significantly higher in RA than in OA synovial fluids.
Conclusion: Because TSA sensitises RASF for TRAIL-induced apoptosis, it is concluded that TSA discloses sensitive sites in the cascade of TRAIL signalling and may represent a new principle for the treatment of RA.
Abbreviations: HDAC, histone acetylation/deacetylation; OA, osteoarthritis; RA, rheumatoid arthritis; RASF, rheumatoid arthritis synovial fibroblasts; TBST, Tris buffered saline containing 0.1% Tween 20; TRAIL, tumour necrosis factor related apoptosis-inducing ligand; TSA, trichostatin A
Keywords: trichostatin A; TRAIL; apoptosis; synovial fibroblasts; rheumatoid arthritis
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