Overexpression of Toll-like Receptors 3 and 4 in Synovial Tissue From Patients With Early Rheumatoid Arthritis Toll-like Receptor Expression in Early and Longstanding Arthritis

被引:273
作者
Ospelt, Caroline [1 ,2 ]
Brentano, Fabia [1 ,2 ]
Rengel, Yvonne [1 ,2 ]
Stanczyk, Joanna [1 ,2 ]
Kolling, Christoph [3 ]
Tak, Paul P. [4 ]
Gay, Renate E. [1 ,2 ]
Gay, Steffen [1 ,2 ]
Kyburz, Diego [1 ,2 ]
机构
[1] Univ Zurich Hosp, Ctr Expt Rheumatol, CH-8091 Zurich, Switzerland
[2] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
[3] Schulthess Clin, Zurich, Switzerland
[4] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands
来源
ARTHRITIS AND RHEUMATISM | 2008年 / 58卷 / 12期
关键词
D O I
10.1002/art.24140
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. To analyze the expression, regulation, and biologic relevance of Toll-like receptors (TLRs) 1-10 in synovial and skin fibroblasts and to determine the expression levels of TLRs 2, 3, and 4 in synovial tissues from patients with early rheumatoid arthritis (RA), longstanding RA, and osteoarthritis (OA). Methods. Expression of TLRs 1-10 in RA synovial fibroblasts (RASFs), OASFs, and skin fibroblasts was analyzed by real-time polymerase chain reaction (PCR). Fibroblasts were stimulated with tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta), bacterial lipopeptide, poly(I-C), lipopolysaccharide, and flagellin. Production of IL-6 was determined by enzyme-linked immunosorbent assay and induction of TLRs 2-5, matrix metalloproteinases (MMPs) 3 and 13 messenger RNA by real-time PCR. Expression of TLRs 2-4 in synovial tissues was analyzed by immunohistochemistry. Results. Synovial fibroblasts expressed TLRs 1-6, but not TLRs 7-10. Among the expressed TLRs, TLR-3 and TLR-4 were the most abundant in synovial fibroblasts, and stimulation of synovial fibroblasts with the TLR-3 ligand poly(I-C) led to the most pronounced increase in IL-6, MMP-3, and MMP-13. In contrast, skin fibroblasts did not up-regulate MMP-3 or MMP-13 after stimulation with any of the tested stimuli. In synovial tissues from patients with early RA, TLR-3 and TLR-4 were highly expressed and were comparable to the levels of patients with longstanding RA. These expression levels were elevated as compared with those in OA. Conclusion. Our findings of high expression of TLRs, particularly TLRs; 3 and 4, at an early stage of RA and the reactivity of synovial fibroblasts in vitro to TLR ligands suggest that TLR signaling pathways resulting in persistent inflammation and joint destruction are activated early in the disease process.
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页码:3684 / 3692
页数:9
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