Trichostatin A cooperates with Fas-mediated signal to induce apoptosis in rheumatoid arthritis synovial fibroblasts.

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 p21(WAF1/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.

• Authors: Akio Morinobu, Biao Wang, Jun Liu, Shinichi Yoshiya, Masahiro Kurosaka, Shunichi Kumagai
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 33 Issue 6 Pg. 1052-60 (Jun 2006) ISSN: 0315-162X [Print] Canada
• PMID: 16755652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Drug Combinations
• Enzyme Inhibitors
• Hydroxamic Acids
• RNA, Messenger
• fas Receptor
• trichostatin A

Topics

• Apoptosis (drug effects)
• Arthritis, Rheumatoid
• Cell Survival (drug effects)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (drug effects, metabolism, pathology)
• Flow Cytometry
• Fluorescent Antibody Technique, Indirect
• Humans
• Hydroxamic Acids (pharmacology)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Synovial Membrane (drug effects, metabolism, pathology)
• fas Receptor (pharmacology)