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

Abstract

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 PGE 2 . 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-␣ 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 PGE 2 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. ( J. Clin. Invest. 1996. 97:2672-2679.)

Microsomal Prostaglandin E Synthase-1 Is a Major Terminal Synthase That Is Selectively Up-Regulated During Cyclooxygenase-2-Dependent Prostaglandin E2 Production in the Rat Adjuvant-Induced Arthritis Model

“…Selective COX-2 inhibitors reduce the pain and inflammation in AIA along with a corresponding decrease of PGE 2 in the inflamed paw in this model (24,25). It has recently been shown that a selective COX-1 inhibitor that does not inhibit the inflammation in AIA also does not result in inhibition of PGE 2 in the paw (26).…”

Cloricromene, a coumarine derivative, protects against collagen‐induced arthritis in Lewis rats

“…As the levels of TNFa and IL-1 as well as the induction of iNOS are signi®cantly lower in the plasma obtained from cloricromene-treated rats, it is not surprising that the degree of COX-2 induction is also signi®cantly attenuated in the joints of cloricromene-treated rats. There is good evidence in this and in other models of in¯ammation that an enhanced formation of prostanoids following the induction of COX-2 contributes to the pathophysiology of local and systemic in¯ammation (Salvemini et al, 1995;Anderson et al, 1996) and also that selective inhibitors of COX-2 exert potent anti-in¯ammatory e ects (Anderson et al, 1996;Mitchell et al, 1993;Harada et al, 1996).…”

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

“…In preliminary experiments, the non-selective cyclooxygenase inhibitor sulindac sul®de and inhibited the proliferatioan of RIE-Tr cells in culture (data not shown). We next used a selective cyclooxygenase-2 inhibitor, SC-58125, (Seibert et al, 1994;Anderson et al, 1996;Masferrer et al, 1996) to treat the cultured cells. SC-58125 had no signi®cant e ect on growth of the RIE-1 parental cells (Figure 5a), but inhibited RIE-Tr cell growth in a concentrationa-dependent manner.…”