Endogenous interleukin-6, but not tumor necrosis factor alpha, contributes to the development of toll-like receptor 4/myeloid differentiation factor 88-mediated acute arthritis in mice

Arthritis Rheum. 2005 Aug;52(8):2530-40. doi: 10.1002/art.21213.


Objective: 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.

Methods: 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-gamma, and tumor necrosis factor alpha (TNFalpha), were sequentially treated with ECW and LPS.

Results: 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 TNFalpha 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.

Conclusion: Our present results clearly indicate the importance of priming with ECW and the requirement of TLR-4/MyD88-mediated IL-6, but not TNFalpha, for the development of ECW/LPS-induced arthritis. LPS-induced IL-6, in the absence of TNFalpha, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / metabolism*
  • Arthritis / chemically induced
  • Arthritis / metabolism*
  • Cell Extracts
  • Cell Wall / chemistry
  • Cytokines / metabolism
  • Escherichia coli
  • Interferon-gamma / metabolism
  • Interleukin-6 / metabolism*
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88
  • Receptors, Immunologic / metabolism*
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cell Extracts
  • Cytokines
  • Interleukin-6
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Immunologic
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma