Endogenous interleukin-6, but not tumor necrosis factor α, contributes to the development of toll-like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice
Article first published online: 28 JUL 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 8, pages 2530–2540, August 2005
How to Cite
Kyo, F., Futani, H., Matsui, K., Terada, M., Adachi, K., Nagata, K., Sano, H., Tateishi, H., Tsutsui, H. and Nakanishi, K. (2005), Endogenous interleukin-6, but not tumor necrosis factor α, contributes to the development of toll-like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice. Arthritis & Rheumatism, 52: 2530–2540. doi: 10.1002/art.21213
- Issue published online: 28 JUL 2005
- Article first published online: 28 JUL 2005
- Manuscript Accepted: 3 MAY 2005
- Manuscript Received: 24 AUG 2004
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- The Osaka Foundation for Promotion of Clinical Immunology
- Hyogo College of Medicine
To generate a mouse model of reactive arthritis (ReA), an aseptic synovitis that develops in joints distant from the primary bacterial infection site, to examine roles for Toll-like receptors (TLRs) that recognize bacterial components involved in the development of this arthritis, and to identify the cytokine(s) relevant to this arthritis.
Mice were treated with cell wall extract from Escherichia coli (ECW) gram-negative bacterium by injection into the footpads. Seven days later, the mice were challenged with lipopolysaccharide (LPS), a TLR-4 ligand, which was injected into the knee joint cavity. To investigate the cytokine(s) involved in this arthritis, mice deficient in various arthritogenic cytokines, such as interleukin-6 (IL-6), IL-12, IL-18, interferon-γ, and tumor necrosis factor α (TNFα), were sequentially treated with ECW and LPS.
ECW-primed mice manifested acute severe arthritis after intraarticular challenge with ECW or LPS, while unprimed mice exhibited modest changes after these challenges. Mutant mice lacking functional TLR-4 or myeloid differentiation factor 88 (MyD88), an adaptor molecule of TLR-4 signaling, were resistant to this arthritis. Although both TNFα and IL-6 were equally expressed in the joint after LPS challenge, Il6−/− mice, but not Tnf−/− mice, were resistant to ECW/LPS-induced arthritis.
Our present results clearly indicate the importance of priming with ECW and the requirement of TLR-4/MyD88–mediated IL-6, but not TNFα, for the development of ECW/LPS-induced arthritis. LPS-induced IL-6, in the absence of TNFα, mediates LPS-induced arthritis. These results suggest that IL-6 is a rational target for therapeutic regimens for inflammatory arthritis, including ReA and rheumatoid arthritis.