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Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis.
Ann Rheum Dis. 2006 Jul; 65(7):910-2.AR

Abstract

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 micromol/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.

Authors+Show Affiliations

Centre of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH 8091 Zurich, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16284094

Citation

Jüngel, A, et al. "Trichostatin a Sensitises Rheumatoid Arthritis Synovial Fibroblasts for TRAIL-induced Apoptosis." Annals of the Rheumatic Diseases, vol. 65, no. 7, 2006, pp. 910-2.
Jüngel A, Baresova V, Ospelt C, et al. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann Rheum Dis. 2006;65(7):910-2.
Jüngel, A., Baresova, V., Ospelt, C., Simmen, B. R., Michel, B. A., Gay, R. E., Gay, S., Seemayer, C. A., & Neidhart, M. (2006). Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Annals of the Rheumatic Diseases, 65(7), 910-2.
Jüngel A, et al. Trichostatin a Sensitises Rheumatoid Arthritis Synovial Fibroblasts for TRAIL-induced Apoptosis. Ann Rheum Dis. 2006;65(7):910-2. PubMed PMID: 16284094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. AU - Jüngel,A, AU - Baresova,V, AU - Ospelt,C, AU - Simmen,B R, AU - Michel,B A, AU - Gay,R E, AU - Gay,S, AU - Seemayer,C A, AU - Neidhart,M, Y1 - 2005/11/10/ PY - 2005/11/15/pubmed PY - 2006/7/18/medline PY - 2005/11/15/entrez SP - 910 EP - 2 JF - Annals of the rheumatic diseases JO - Ann Rheum Dis VL - 65 IS - 7 N2 - 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 micromol/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. SN - 0003-4967 UR - https://www.unboundmedicine.com/medline/citation/16284094/Trichostatin_A_sensitises_rheumatoid_arthritis_synovial_fibroblasts_for_TRAIL_induced_apoptosis_ L2 - https://ard.bmj.com/lookup/pmidlookup?view=long&pmid=16284094 DB - PRIME DP - Unbound Medicine ER -