2005 Fiscal Year Final Research Report Summary
Control and Induction of the arthritis mediated by Toll-like receptor
| Project/Area Number |
16591001
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Hyogo College of Medicine |
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Principal Investigator |
MATSUI Kiyoshi Hyogo College of Medicine, Faculty of Medicine, Assistant professor, 医学部, 講師 (00291815)
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| 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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| Project Period (FY) |
2004 – 2005
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| Keywords | arthritis model / IL-6 / TLR4 / inflammatory cytokine |
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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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