Prostaglandin E2 production dependent upon cyclooxygenase-1 and cyclooxygenase-2 and its contradictory modulation by auranofin in rat peritoneal macrophages.

M Yamada, H Niki, M Yamashita, S Mue, K Ohuchi

Department of Pathophysiological Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

The Journal of pharmacology and experimental therapeutics 1997 May

filter terms:

Rat peritoneal macrophages were incubated in the presence of cycloheximide or dexamethasone to inhibit the induction of cyclooxygenase (COX)-2 protein synthesis. Thereafter, when the macrophages were incubated in the presence of arachidonic acid, PGE2 production was increased. Western blot analysis demonstrated that COX-2 protein levels were low and were not affected by arachidonic acid treatment. COX-1 protein levels were not affected by arachidonic acid treatment either. The COX-2 inhibitors NS-398 and nimesulide only slightly inhibited PGE2 production, whereas the COX-1/COX-2 inhibitors indomethacin, piroxicam and tenoxicam strongly inhibited PGE2 production. This suggests that under these conditions, PGE2 production is dependent on COX-1. After the macrophages were treated with aspirin to inactivate existing COX-1 and COX-2, however, treatment with 12-0-tetradecanoylphorbol 13-acetate increased PGE2 production. Furthermore, COX-2 protein levels were markedly increased by 12-0-tetradecanoylphorbol 13-acetate treatment, whereas COX-1 protein levels did not change. In this case, both the COX-2 and the COX-1/ COX-2 inhibitors inhibited PGE2 production. This suggest that under these conditions, PGE2 production is dependent on COX-2. Effects of auranofin on COX-1-dependent and COX-2-dependent PGE2 production were examined. We found that auranofin stimulated COX-1-dependent PGE2 production but inhibited COX-2-dependent PGE2 production in a concentration-dependent manner. The latter effect was found to be due to the inhibition of COX-2 protein induction. These findings might explain the mechanism of the antirheumatic and anti-inflammatory activities of auranofin.

Citation

M Yamada, H Niki, M Yamashita, S Mue, K Ohuchi. Prostaglandin E2 production dependent upon cyclooxygenase-1 and cyclooxygenase-2 and its contradictory modulation by auranofin in rat peritoneal macrophages. The Journal of pharmacology and experimental therapeutics. 1997 May;281(2):1005-12