PROSTAGLANDIN E-2 PRODUCTION DEPENDENT UPON CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2 AND ITS CONTRADICTORY MODULATION BY AURANOFIN IN RAT PERITONEAL-MACROPHAGES
M. Yamada et al., PROSTAGLANDIN E-2 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, 281(2), 1997, pp. 1005-1012
Rat peritoneal macrophages were incubated in the presence of cyclohexi
mide or dexamethasone to inhibit the induction of cyclooxygenase (COX)
-2 protein synthesis. Thereafter, when the macrophages were incubated
in the presence of arachidonic acid, PGE(2) 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 lev
els were not affected by arachidonic acid treatment either. The COX-2
inhibitors NS-398 and nimesulide only slightly inhibited PGE(2) produc
tion, whereas the COX-1/COX-2 inhibitors indomethacin, piroxicam and t
enoxicam strongly inhibited PGE(2) production. This suggests that unde
r these conditions, PGE(2) production is dependent on COX-1. After the
macrophages were treated with aspirin to inactivate existing COX-1 an
d COX-2, however, treatment with 12-O-tetradecanoylphorbol13-acetate i
ncreased PGE(2) production. Furthermore, COX-2 protein levels were mar
kedly increased by 12-0-tetradecanoylphorbol 13-acetate treatment, whe
reas COX-1 protein levels did not change. In this case, both the COX-2
and the COX-1/COX-2 inhibitors inhibited PGE(2) production. This sugg
ests that under these conditions, PGE(2) production is dependent on CO
X-2. Effects of auranofin on COX-1-dependent and COX-2-dependent PGE(2
) production were examined. We found that auranofin stimulated COX-1-d
ependent PGE(2) production but inhibited COX-2-dependent PGE(2) produc
tion 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 antiinflammatory
activities of auranofin.