The role of TNF-α in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): A study using a human RA/SCID mouse chimera

Abstract

Objective. In order to elucidate which cytokine preferentially stimulates the synovium in patients with rheumatoid arthritis (RA), we investigated the roles of tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6) using SCID mice engrafted with human RA tissue (SCID-HurAg). Methods. The SCID-HuRAg mice were prepared according to our previously described method. First, SCID-HuRAg mice were treated with chimeric anti-TNF-α monoclonal antibody (mAB, 100 μg/mouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 μg of recombinant TNF-α or IL-6 (0.6 μg/h) was administered daily to mice using an osmium pump. The histological changes and serum cytokine levels were examined 4 weeks after the initial administration. Human immunoglobulin G (IgG) was administered to mice as a control. Results. Synovial inflammatory cells were significantly decreased after the anti-TNF-α mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF-α administration. The levels of both IL-6 and TNF-α in sera were significantly increased by recombinant TNF-α administration, while TNF-α levels were unchanged by IL-6 administration. This suggests that TNF-α controls IL-6 production. Despite the profound changes in inflammation, we found no effects on bone and no articular cartilage damage was produced by TNF-α. Conclusion. This study provides strong evidence that TNF-α is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-α regulates IL-6 production. However, other inflammatory pathways independent of TNF-α may contribute to the bone and cartilage damage seen in RA.