Production and regulation of monocyte chemoattractant protein-1 in lipopolysaccharide- or monosodium urate crystal-induced arthritis in rabbits: roles of tumor necrosis factor alpha, interleukin-1, and interleukin-8

Lab Invest. 1998 Aug;78(8):973-85.


The production of monocyte chemoattractant protein-1 (MCP-1) and its regulation by TNFalpha, IL-1, and IL-8 were investigated in two rabbit models of arthritis induced by intra-articular injection of lipopolysaccharide (LPS) or monosodium urate (MSU) crystals. We first prepared recombinant rabbit MCP-1 and antibodies and then developed an immunoassay. The immunoassay detected 3 pg/ml rabbit MCP-1 and did not cross-react with other rabbit chemokines such as IL-8 or GRO. MCP-1 was first detected in synovial fluid (SF) at 1 hour, and peaked at 4 or 2 hours after the injection of LPS or MSU crystals, respectively. Immunohistochemically, MCP-1 was detected in synovial lining cells and infiltrating neutrophils. The amounts of MCP-1 detected in SF from neutrophil-depleted rabbits were similar to those in normal rabbits, suggesting that synovial lining cells were the main source of MCP-1 detected in SF. The peak level of MCP-1 in SF after LPS-injection was inhibited by 57% with anti-TNFalpha mAb and by 41% with IL-1 receptor antagonist (IL-1Ra). Coadministration of anti-TNFalpha mAb and IL-1Ra inhibited 90% of MCP-1 production. In contrast, the peak level of MCP-1 in SF after MSU crystal-injection was not affected by any cytokine inhibitor, but was reduced by 52% with coadministration of anti-TNFalpha mAb and IL-1Ra. Anti-IL-8 IgG had no effect on the production of MCP-1 in either model. Thus, the production of MCP-1 in LPS-induced arthritis was mostly regulated by TNFalpha and IL-1, whereas half the extent of MCP-1 production in MSU crystal-induced arthritis was independent of TNFalpha or IL-1. IL-8 does not seem to regulate the production of MCP-1 in SF either directly or indirectly. Finally, administration of neutralizing anti-MCP-1 antibody inhibited LPS- and MSU crystal-induced monocyte infiltration by 58.4% and 44.9%, respectively, suggesting that synovial production of MCP-1 plays an important role in the recruitment of monocytes in these arthritis models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / biosynthesis
  • Arthritis / chemically induced
  • Arthritis / metabolism*
  • Arthritis / pathology
  • COS Cells
  • Cell Movement / immunology
  • Chemokine CCL2 / analysis
  • Chemokine CCL2 / biosynthesis*
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Crystallization
  • Female
  • Fluoroimmunoassay
  • Immune Sera / administration & dosage
  • Immune Sera / biosynthesis
  • Injections, Intra-Articular
  • Injections, Intravenous
  • Interleukin-1 / physiology*
  • Interleukin-8 / physiology*
  • Knee Joint / pathology
  • Lipopolysaccharides / toxicity*
  • Monocytes / pathology
  • Rabbits
  • Recombinant Proteins / analysis
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / immunology
  • Synovial Fluid / chemistry
  • Tumor Necrosis Factor-alpha / physiology*
  • Uric Acid / toxicity*


  • Antibodies, Monoclonal
  • Chemokine CCL2
  • Immune Sera
  • Interleukin-1
  • Interleukin-8
  • Lipopolysaccharides
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Uric Acid