Differential regulation of cyclooxygenase-2 and matrix metalloproteinase-9 expression in a synovial cell line

Persistent joint inflammation, pain and concomitant joint destruction characterize chronic rheumatoid arthritis. With HIG-82, a rabbit synovial cell line as a model system, two pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1 β, were used to examine whether each cytokine plays a specific role in rheumatoid arthritis. The level of cyclooxygenase-2 expression with prostaglandin E₂ released into the media and the matrix metalloproteinase-9 activity induced by tumor necrosis factor-α and interleukin-1 β were used as in vitro measures of the extent of inflammation and cartilage erosion, respectively.; Tumor necrosis factor-α treatment alone increased cyclooxygenase-2 expression and prostaglandin E₂ production. Tumor necrosis factor-a with a low concentration of interleukin-1 β produced similar cyclooxygenase-2/prostaglandin E₂ levels as compared to the same concentration of tumor necrosis factor-α alone. A cyclooxygenase-2 specific inhibitor, NS-398, and a non-specific cyclooxygenase-1/cyclooxygenase-2 inhibitor, indomethacin, reduced prostaglandin E₂ and matrix metalloproteinase-9 levels considerably following treatment with tumor necrosis factor-α. Neutralizing tumor necrosis factor-α with the anti-tumor necrosis factor-α antibody reduced expression of matrix metalloproteinase-9 along with diminished prostaglandin E₂ levels. On the other hand, interleukin-1 β alone did not have effect on cyclooxygenase-2 expression/prostaglandin E₂ production and matrix metal loproteinase-9 activity, suggesting that HIG-82 cells may be devoid of interleukin-1 receptors. The data provide a framework for uncoupling of cyclooxygenase-2 and matrix metalloproteinase-9 expression in synoviocytes. The pathways by which inflammatory and tissue destructive changes occur in rheumatoid arthritis underlie the need for approaches in reducing the levels of tumor necrosis factor-α/interleukin-1 β in directed combination therapy.