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Prostaglandins formed by the cyclooxygenase (COX) en-zymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflam-mation in rat adjuvant arthritis was evaluated by character-ization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE 2. PG pro-duction was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-a and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administra-tion of a selective COX-2 inhibitor, SC-58125, rapidly re-versed paw edema and reduced the level of PGE 2 in paw tis-sue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Fur-thermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adju-vant arthritis and that COX-2 derived PGs upregulat