Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis

Objective. Prostaglandins (PGs) are found in high levels in the synovial fluid of patients with rheumatoid arthritis, and nonsteroidal blockade of these bioactive lipids plays a role in patient care. The aim of this study was to explore the relative contribution of cyclooxygenase (COX) isoforms and PG species in the autoantibody-driven K/BxN serum-transfer arthritis. Methods. The prostanoid content of arthritic ankles was assessed in ankle homogenates, and the importance of this pathway was confirmed with pharmacologic blockade. The presence of COX isoforms was assessed by Western blotting and their functional contribution was compared using COX-1(-/-) and COX-2(-/-) mice as well as isoform-specific inhibitors. The relative importance of PGE(2) and PGI(2) (prostacyclin) was determined using mice deficient in microsomal PGE synthase 1 (mPGES-1) and in the receptors for PGI(2). Results. High levels of PGE(2) and 6-keto-PGF(1 alpha) (a stable metabolite of PGI(2)) were detected in arthritic joint tissues, correlating strongly with the intensity of synovitis. Pharmacologic inhibition of PG synthesis prevented arthritis and ameliorated active disease. While both COX isoforms were found in inflamed joint tissues, only COX-1 contributed substantially to clinical disease; COX-1(-/-) mice were fully resistant to disease, whereas COX-2(-/-) mice remained susceptible. These findings were confirmed by isoform-specific pharmacologic inhibition. Mice lacking mPGES-1 (and therefore PGE(2)) developed arthritis normally, whereas mice incapable of responding to PGI(2) exhibited a significantly attenuated arthritis course, confirming a role of PGI(2) in this arthritis model. Conclusion. These findings challenge previous paradigms of distinct housekeeping versus inflammatory functions of the COX isoforms and highlight the potential pathogenic contribution of prostanoids synthesized via COX-1, in particular PGI(2), to inflammatory arthritis.