Abstract:
:The transcription factor STAT-1 (signal transducer and activator of transcription-1) plays a pivotal role in the expression of inflammatory gene products involved in the pathogenesis of arthritis such as various cytokines and the CD40/CD40 ligand (CD40/CD40L) receptor-ligand dyad. The therapeutic efficacy of a synthetic decoy oligodeoxynucleotide (ODN) binding and neutralizing STAT-1 was tested in murine antigen-induced arthritis (AIA) as a model for human rheumatoid arthritis (RA). The STAT-1 decoy ODN was injected intra-articularly in methylated bovine serum albumin (mBSA)-immunized mice 4 h before arthritis induction. Arthritis was evaluated by joint swelling measurement and histological evaluation and compared to treatment with mutant control ODN. Serum levels of pro-inflammatory cytokines, mBSA-specific antibodies and auto-antibodies against matrix constituents were assessed by enzyme-linked immunosorbent assay (ELISA). The transcription factor neutralizing efficacy of the STAT-1 decoy ODN was verified in vitro in cultured synoviocytes and macrophages. Single administration of STAT-1 decoy ODN dose-dependently suppressed joint swelling and histological signs of acute and chronic arthritis. Delayed-type hypersensitivity (DTH) reaction, serum levels of interleukin-6 (IL-6) and anti-proteoglycan IgG titres were significantly reduced in STAT-1 decoy ODN-treated mice, whereas mBSA, collagen type I and type II specific immunoglobulins were not significantly affected. Intra-articular administration of an anti-CD40L (anti-CD154) antibody was similarly effective. Electrophoretic mobility shift analysis (EMSA) of nuclear extracts from synoviocytes incubated with the STAT-1 decoy ODN in vitro revealed an inhibitory effect on STAT-1. Furthermore, the STAT-1 decoy ODN inhibited the expression of CD40 mRNA in stimulated macrophages. The beneficial effects of the STAT-1 decoy ODN in experimental arthritis presumably mediated in part by affecting CD40 signalling in macrophages may provide the basis for a novel treatment of human RA.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Hückel M,Schurigt U,Wagner AH,Stöckigt R,Petrow PK,Thoss K,Gajda M,Henzgen S,Hecker M,Bräuer Rdoi
10.1186/ar1869keywords:
subject
Has Abstractpub_date
2006-01-01 00:00:00pages
R17issue
1eissn
1478-6354issn
1478-6362pii
ar1869journal_volume
8pub_type
杂志文章abstract::The changes occurring in the field of rheumatoid arthritis (RA) over the past decade or two have encompassed new therapies and, in particular, a new look at the clinical characteristics of the disease in the context of therapeutic improvements. It has been shown that composite disease activity indices have special mer...
journal_title:Arthritis research & therapy
pub_type: 杂志文章,评审
doi:10.1186/ar2535
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pub_type: 杂志文章,评审
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journal_title:Arthritis research & therapy
pub_type: 评论,社论
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更新日期:2010-01-01 00:00:00
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更新日期:2012-11-01 00:00:00
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更新日期:2013-01-01 00:00:00
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journal_title:Arthritis research & therapy
pub_type: 杂志文章
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更新日期:2005-01-01 00:00:00
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更新日期:2007-01-01 00:00:00
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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更新日期:2014-04-10 00:00:00
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更新日期:2016-04-26 00:00:00
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pub_type: 杂志文章,meta分析
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更新日期:2011-01-01 00:00:00
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