Down-regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas-mediated apoptosis

被引:50
|
作者
Palao, G [1 ]
Santiago, B [1 ]
Galindo, M [1 ]
Payá, M [1 ]
Ramirez, JC [1 ]
Pablos, JL [1 ]
机构
[1] Hosp 12 Octubre, Serv Reumatol, E-28041 Madrid, Spain
来源
ARTHRITIS AND RHEUMATISM | 2004年 / 50卷 / 09期
关键词
D O I
10.1002/art.20453
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. Hyperplasia of fibroblast-like synoviocytes (FLS) contributes to chronic inflammation and joint destruction in rheumatoid arthritis (RA). FLICE-inhibitory protein (FLIP) is an antiapoptotic protein that might prevent apoptotic elimination of FLS in response to death ligands such as tumor necrosis factor alpha (TNFalpha) or Fas ligand, which are present in RA synovium. Previous studies on FLIP expression by osteoarthritis (OA) and RA FLS have shown variable results, and the specific role of FLIP as an apoptosis inhibitor in these cells remains unclear. We undertook this study to investigate the expression and antiapoptotic function of FLIP in FLS. Methods. We studied the expression of FLIP by immunohistochemistry and immunoblotting in synovial tissues or cultured FLS from RA and OA patients. FLS apoptosis was induced by an agonistic anti-Fas monoclonal antibody and FLS were then quantified. We studied the effects of cycloheximide (CHX), TNFalpha, and FLIP antisense oligonucleotide on FLIP expression and FLS apoptotic susceptibility. Results. FLIPL was the isoform mainly expressed in lining synoviocytes and cultured FLS. Synovial tissues and cultured FLS from OA and RA tissues displayed similar patterns and levels of expression of FLIP. Fas-induced apoptosis was variable in different FLS lines, but differences between OA and RA groups were not detected. TNFalpha induced increases in FLIPL and FLIPS expression and protected RA FLS from apoptosis, while CHX induced the opposite effects. Downregulation of FLIP by antisense oligonucleotide strongly sensitized RA FLS to Fas-mediated apoptosis. Conclusion. Apoptosis susceptibility and FLIP expression are similar in OA and RA FLS. Downregulation of FLIP sensitizes RA FLS to Fas-mediated apoptosis and may be a valuable tool for targeting RA FLS hyperplasia.
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收藏
页码:2803 / 2810
页数:8
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