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Trichostatin A Cooperates with Fas-Mediated Signal to Induce Apoptosis in Rheumatoid Arthritis Synovial Fibroblasts
AKIO MORINOBU, BIAO WANG, JUN LIU, SHINICHI YOSHIYA, MASAHIRO KUROSAKA, and SHUNICHI KUMAGAI ABSTRACT. Objective. To clarify the effects of trichostatin A (TSA), a histone deacetylase inhibitor, on the growth and survival of rheumatoid arthritis synovial fibroblasts (RA-SF). Methods. Cell viability was assessed using a WST-8 assay and direct cell counting. Apoptosis was detected by annexin V staining on a flow cytometer. Protein and mRNA expression was determined by Western blotting, flow cytometry, and RT-PCR. Results. TSA suppressed cell growth of RA-SF in a dose-dependent manner, as determined by WST-8 assay and direct cell counting. Other histone deacetylase inhibitors also showed inhibitory effects on RA-SF proliferation. TSA upregulated p21WAF1/CIP1 cell cycle inhibitor, suggesting that cell cycle arrest is involved in the reduction of cell numbers. In addition, TSA cooperated with Fas-induced pathway to induce cell death, determined by WST-8 assay and annexin V staining. TSA reduced FLICE inhibitory protein (FLIP) expression but not Bcl-2, Bcl-XL, and Fas expression, indicating that the synergistic effect may be through downregulation of FLIP. Conclusion. TSA has antirheumatic effects on RA-SF and might be a potential therapeutic tool for the treatment of RA. (J Rheumatol 2006;33:1052–60) Key Indexing Terms:
RHEUMATOID ARTHRITIS From the Departments of Clinical Pathology and Immunology, and Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. Supported in part by a grant-in-aid for scientific research (16590981) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. A. Morinobu, MD, PhD, Lecturer; B. Wang, MD, Graduate Student; J. Liu, MD, Graduate Student, Department of Clinical Pathology and Immunology; S. Yoshiya, MD, PhD, Associate Professor, Department of Orthopaedic Surgery; S. Kumagai, MD, PhD, Professor, Department of Clinical Pathology and Immunology. Address reprint requests to Dr. A. Morinobu, Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: morinobu@med.kobe-u.ac.jp Accepted for publication January 3, 2006.
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