Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

GD Anderson, SD Hauser, KL McGarity… - The Journal of …, 1996 - Am Soc Clin Investig
GD Anderson, SD Hauser, KL McGarity, ME Bremer, PC Isakson, SA Gregory
The Journal of clinical investigation, 1996Am Soc Clin Investig
Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of
inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in
rat adjuvant arthritis was evaluated by characterization 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 PGE2. PG
production was associated with upregulation of COX-2 mRNA and protein in the affected …
Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization 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 PGE2. PG production 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-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue 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. Furthermore, 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 adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.
The Journal of Clinical Investigation