Prostaglandin E2 production dependent upon cyclooxygenase-1 and cyclooxygenase-2 and its contradictory modulation by auranofin in rat peritoneal macrophages.
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.
Yamada
M
M
Department of Pathophysiological Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Niki
H
H
Yamashita
M
M
Mue
S
S
Ohuchi
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D007527:Isoenzymes / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008565:Membrane Proteins; D001310:Auranofin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone