Abstract | OBJECTIVE: METHODS: Primary human monocyte-derived macrophages and dendritic cells (DCs) were used to overexpress SIGIRR as well as to knock down endogenously expressed SIGIRR using small interfering RNAs. SIGIRR was also overexpressed in synovial cells derived from RA patients. To investigate the role of SIGIRR in vivo, zymosan-induced arthritis (ZIA) and collagen antibody-induced arthritis (CAIA) were induced in SIGIRR-knockout mice. RESULTS: SIGIRR overexpression inhibited TLR-induced cytokine production in macrophages and DCs, while SIGIRR knockdown resulted in increased cytokine production following TLR stimulation. Moreover, SIGIRR overexpression inhibited the spontaneous release of cytokines by human RA synovial cells. The role of SIGIRR as an inhibitor of inflammation was confirmed in vivo, since SIGIRR(-/-) mice developed a more severe disease in both the ZIA and CAIA models. CONCLUSION: Our study is the first to show the expression pattern and function of SIGIRR in primary human cells. Furthermore, this investigation defines the role of SIGIRR in disease-relevant cell types and demonstrates that SIGIRR is a potential therapeutic target for RA.
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Authors | Stefan K Drexler, Philip Kong, Julia Inglis, Richard O Williams, Cecilia Garlanda, Alberto Mantovani, Amir S Yazdi, Fionula Brennan, Marc Feldmann, Brian M J Foxwell |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 62
Issue 8
Pg. 2249-61
(Aug 2010)
ISSN: 1529-0131 [Electronic] United States |
PMID | 20506350
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Small Interfering
- Receptors, Interleukin-1
- TIR8 protein, human
- Toll-Like Receptors
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Topics |
- Animals
- Arthritis, Experimental
(genetics, immunology, metabolism)
- Arthritis, Rheumatoid
(genetics, immunology, metabolism)
- Blotting, Western
- Dendritic Cells
(immunology, metabolism)
- Gene Transfer Techniques
- Humans
- Inflammation
(genetics, immunology, metabolism)
- Macrophages
(immunology, metabolism)
- Mice
- Mice, Knockout
- RNA Interference
- RNA, Small Interfering
- Receptors, Interleukin-1
(genetics, immunology, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
(genetics, immunology)
- Toll-Like Receptors
(genetics, immunology, metabolism)
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