Inhibition by nimesulide of prostaglandin production in rat macrophages

We have investigated the inhibitory action of nimesulide (4-nitro-2-phenoxymethanesulfonanilide) on release of prostaglandin E2 (PGE2) from rat peritoneal exudated macrophages (macrophages) and its mechanism of action. PGE2 release from macrophages stimulated with opsonized zymosan (OPZ) were increased in the 20 h after stimulation, whereas no significant increase was noted in PGE2 release from unstimulated macrophages. Nimesulide caused a weak inhibition of PGE2 release from macrophages at 15 min after OPZ stimulation as compared with indomethacin, but nimesulide caused approximately the same strong inhibition as indomethacin at 10 h after OPZ stimulation. Cellular cyclooxygenase (COX) activity in macrophage at 10 h after OPZ stimulation was increased approximately seven times the COX activity in macrophages before OPZ stimulation. Nimesulide caused approximately the same strong inhibition of cellular COX activity as indomethacin at 10 h after OPZ stimulation. COX-1 mRNA was expressed in macrophages irrespective of OPZ stimulation, 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 nor the levels of COX-2 protein at 10 h after OPZ stimulation. In contrast, actinomycin D caused strong inhibition of COX-2 mRNA expression and protein induction. These results suggest that inhibition by nimesulide of PGE2 release from macrophages, namely inflammatory cells, would be neither due to inhibition of COX-2 mRNA expression nor COX-2 induction, but to the selective inhibition of COX-2 activity itself.