Taniguchi Y, Yokoyama K, Ikesue A, Noda K, Debuchi H, Nakamura T, Toda A, Shimeno H
Hisamitsu Pharmaceutical Co., Inc., Saga, Japan.
Drugs Exp Clin Res. 1998;24(1):17-27.
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.
我们研究了尼美舒利（4-硝基-2-苯氧甲基磺酰苯胺）对大鼠腹腔渗出巨噬细胞（巨噬细胞）释放前列腺素E2（PGE2）的抑制作用及其作用机制。用调理酵母聚糖（OPZ）刺激巨噬细胞后，PGE2的释放在刺激后20小时增加，而未刺激的巨噬细胞中PGE2的释放没有显著增加。与吲哚美辛相比，尼美舒利在OPZ刺激后15分钟对巨噬细胞释放PGE2有较弱的抑制作用，但在OPZ刺激后10小时，尼美舒利产生的抑制作用与吲哚美辛大致相同。OPZ刺激后10小时，巨噬细胞中的细胞环氧化酶（COX）活性比OPZ刺激前巨噬细胞中的COX活性增加了约7倍。在OPZ刺激后10小时，尼美舒利对细胞COX活性的抑制作用与吲哚美辛大致相同。无论是否有OPZ刺激，COX-1 mRNA均在巨噬细胞中表达，但COX-2 mRNA仅在OPZ刺激后表达，且COX-2蛋白同时被诱导。尼美舒利在OPZ刺激后4小时既不影响COX-1 mRNA和COX-2 mRNA的水平，也不影响OPZ刺激后10小时COX-2蛋白的水平。相反，放线菌素D对COX-2 mRNA表达和蛋白诱导有强烈抑制作用。这些结果表明，尼美舒利对巨噬细胞（即炎症细胞）释放PGE2的抑制作用既不是由于抑制COX-2 mRNA表达也不是由于COX-2诱导，而是由于对COX-2活性本身的选择性抑制。
