Bondeson J, Sundler R
Department of Medical and Physiological Chemistry, Malmö General Hospital, Lund University, Sweden.
J Leukoc Biol. 1993 Oct;54(4):329-35. doi: 10.1002/jlb.54.4.329.
The effects of antirheumatic gold compounds and D-penicillamine on protein kinase C- and Ca(2+)-mediated activation of arachidonate mobilization and the formation of eicosanoids in mouse macrophages have been investigated. Auranofin (0.2-2 microM) enhanced the response to phorbol ester two- to three-fold, and similar enhancement was caused by aurothiomalate, aurothioglucose, and penicillamine, but only after pretreatment for 1-4 h. The enhanced mobilization of arachidonate was accompanied by increased formation and release of prostaglandin E2 and 6-keto prostaglandin F1 alpha, but not of lipoxygenase metabolites. No such enhancement occurred when the arachidonate-mobilizing phospholipase A2 was activated directly (calcium ionophore A23187). Instead, auranofin caused selective inhibition of calcium ionophore-induced formation of leukotriene C4. Treatment of macrophages with 4 beta-phorbol 12-myristate 13-acetate causes a rapid increase in the phosphorylation and a 1.4-1.8-fold increase in the activity of the 85-kd arachidonate-mobilizing phospholipase A2 as determined in an in vitro assay. The increase in activity was further enhanced by both the gold compounds and penicillamine. These findings indicate that the target for the enhancing effect of the antirheumatic drugs is located between protein kinase C and phospholipase A2 in the signal chain leading to activation of the latter enzyme.
已研究了抗风湿金化合物和D-青霉胺对蛋白激酶C及Ca(2+)介导的小鼠巨噬细胞花生四烯酸动员激活和类二十烷酸形成的影响。金诺芬（0.2 - 2 microM）使对佛波酯的反应增强2至3倍，硫代苹果酸金钠、硫代葡萄糖金和青霉胺也产生类似增强作用，但仅在预处理1 - 4小时后出现。花生四烯酸动员增强伴随着前列腺素E2和6 - 酮前列腺素F1α的形成及释放增加，但脂氧合酶代谢产物未增加。当直接激活花生四烯酸动员的磷脂酶A2（钙离子载体A23187）时未出现这种增强作用。相反，金诺芬导致选择性抑制钙离子载体诱导的白三烯C4形成。用4β-佛波醇12 - 肉豆蔻酸酯13 - 乙酸酯处理巨噬细胞会使85 kd花生四烯酸动员磷脂酶A2的磷酸化迅速增加，且体外测定其活性增加1.4 - 1.8倍。金化合物和青霉胺均进一步增强了活性增加。这些发现表明抗风湿药物增强作用的靶点位于导致后者酶激活的信号链中蛋白激酶C和磷脂酶A2之间。
