INHIBITION BY NIMESULIDE OF PROSTAGLANDIN PRODUCTION IN RAT MACROPHAGES

We have investigated the inhibitory action of nimesulide (4-nitro-2-ph enoxymethanesulfonanilide) an release of prostaglandin E-2 (PGE(2)) fr om rat peritoneal exudated macrophages (macrophages) and its mechanism of action. PGE(2) release from macrophages stimulated with opsonized zymosan (OPZ) were increased in the 20 h after stimulation, whereas no significant increase was noted in PGE(2) release from unstimulated ma crophages. Nimesulide caused a weak inhibition of PGE(2) release from macrophages at 15 min after OPZ stimulation as compared with indometha cin, but nimesulide caused approximately the same strong inhibition as indomethacin at 10 h after OPZ stimulation. Cellular cyclooxygenase ( COX) activity in macrophages at 10 h after OPZ stimulation was increas ed approximately seven times the COX activity in macrophages before OP Z stimulation. Nimesulide caused approximately the same strong inhibit ion of cellular COX activity as indomethacin at 10 h after OPZ stimula tion. COX-1 mRNA was expressed in macrophages irrespective of OPZ stim ulation, but COX-2 mRNA was expressed only after OPZ stimulation, and COX-2 protein was simultaneously induced. Nimesulide affected neither the levels of COX-1 mRNA and COX-2 mRNA at 4 h after OPZ stimulation n or the levels of COX-2 protein at 10 h after OPZ stimulation. In contr ast, actinomycin D caused strong inhibition of COX-2 mRNA expression a nd protein induction. These results suggest that inhibition by nimesul ide of PGE(2) release from macrophages, namely inflammatory cells, wou ld be neither due to inhibition of COX-2 mRNA expression nor COX-2 ind uction, but to the selective inhibition of COX-2 activity itself.