| Co-Investigator(Kenkyū-buntansha) |
NAKANISHI Kenji Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (60172350)
SANO Hajime Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (00196304)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Objective. To generate a mouse model for reactive arthritis, an aseptic synovitis, which develops at the joints distant from the primary bacterial infection sites, to examine roles for Toll-like receptors (TLRs) which recognize the bacterial components in the development of this arthritis, and to identify the cytokine(s) relevant to this arthritis.
Methods. Mice were treated with cell wall extract from Escherichia coli (ECW), Gram-negative bacterium, at footpads and 7 days later challenged with lipopolysaccharide (LPS), a TLR4 ligand into their knee joint cavity. To investigate the cytokine(s) involved in this arthritis, mice deficient in various arthritogenic cytokines, such as IL-6, IL-12, IL-18, IFN-γ and TNF-α, were sequentially treated with ECW and LPS.
Results. ECW-primed mice manifested acute severe arthritis after intra-articular challenge with ECW or LPS, while unprimed mice exhibited modest changes after these challenges. Mutant mice lacking functional TLR4 or myeloid differentiation factor 88, an adaptor molecule of TLR4 signalings, were resistant to this arthritis. Although both TNF-α and IL-6 were equally expressed in the joint after LPS challenge, II-6^<-/-> mice, but not Tnf^</-> mice, were resistant to the ECW/LPS-induced arthritis.
Conclusion. Our present results clearly indicate the importance of the priming with ECW and the requirement of the TLR4/MyD88-mediated IL-6, but not TNF-α, for the development of ECW/LPS-induced arthritis. IL-6, directly induced in the absence of TNR-α by LPS challenge, mediates LPS-induced arthritis.
These results suggest that IL-6 is a rational target for therapeutic regimens against inflammatory arthritis including reactive arthritis and rheumatoid arthritis.
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