Fantone J C, Marasco W A, Elgas L J, Ward P A
Am J Pathol. 1984 Apr;115(1):9-16.
Prostaglandins (PGs) of the E series and PGI2 have been shown to inhibit acute inflammatory reactions in vivo and polymorphonuclear leukocyte (PMN), chemotaxis, lysosomal enzyme release, and superoxide anion (O-2) production in vitro. This inhibition of neutrophil stimulation by PGEs and PGI2 has been correlated with their ability to increase intracellular cyclic adenosine monophosphate (cAMP) levels. However, the mechanism(s) by which PGEs and PGI2 alter the complex biochemical and biophysical events associated with stimulus-response coupling in the neutrophil are not clear. It is reported here that both PGEs and PGI2 in micromolar concentrations inhibit formyl-methionyl-leucyl-phenylalanine (FMLP)- and zymosan-induced lysosomal enzyme secretion and superoxide anion production in a dose-dependent manner. No preincubation time of PMNs with the prostaglandins is required for inhibition. Addition of PGEs 10 seconds or later after FMLP stimulation does not alter the biologic response of the neutrophils to the stimulus, suggesting that the prostaglandin inhibition effects early events associated with stimulus-response coupling in the neutrophil. Prostaglandin inhibition of lysosomal enzyme release by the calcium ionophore A23187 was overcome by increasing the extracellular ionophore and/or calcium concentration, suggesting that PGs may modulate intracellular free calcium levels in a manner similar to that observed with platelets. Inhibition of phorbol myristate acetate (PMA)-induced neutrophil lysosomal enzyme secretion by PGEs and PGI2 was overcome by increasing concentrations of PMA. However, neither PGEs nor PGI2 altered O-2 production by PMA-treated neutrophils. These data indicate a dissociation between PMA-stimulated O-2 production and lysosomal enzyme release. These findings are consistent with the hypothesis that inhibition of neutrophil stimulation by PGEs and PGI2 is a result of increased intracellular cyclic AMP levels and modulation of calcium-dependent events. In addition, the data indicate that there are at least two mechanisms by which PMNs can be stimulated to produce O-2, one inhibited by PGEs and PGI2 and a second independent of prostaglandin modulation.
E 系列前列腺素（PGs）和前列环素（PGI2）已被证明在体内可抑制急性炎症反应，在体外可抑制多形核白细胞（PMN）的趋化性、溶酶体酶释放及超氧阴离子（O-2）生成。PGEs 和 PGI2 对中性粒细胞刺激的这种抑制作用与其增加细胞内环磷酸腺苷（cAMP）水平的能力相关。然而，PGEs 和 PGI2 改变中性粒细胞中与刺激 - 反应偶联相关的复杂生化和生物物理事件的机制尚不清楚。本文报道，微摩尔浓度的 PGEs 和 PGI2 均以剂量依赖方式抑制甲酰甲硫氨酰亮氨酰苯丙氨酸（FMLP）和酵母聚糖诱导的溶酶体酶分泌及超氧阴离子生成。不需要中性粒细胞与前列腺素进行预孵育时间即可产生抑制作用。在 FMLP 刺激后 10 秒或更晚添加 PGEs 不会改变中性粒细胞对刺激的生物学反应，这表明前列腺素抑制与中性粒细胞刺激 - 反应偶联相关的早期事件。通过增加细胞外离子载体和/或钙浓度可克服前列腺素对钙离子载体 A23187 诱导的溶酶体酶释放的抑制作用，这表明 PGs 可能以类似于在血小板中观察到的方式调节细胞内游离钙水平。通过增加佛波酯（PMA）的浓度可克服 PGEs 和 PGI2 对 PMA 诱导的中性粒细胞溶酶体酶分泌的抑制作用。然而，PGEs 和 PGI2 均未改变经 PMA 处理的中性粒细胞的 O-2 生成。这些数据表明 PMA 刺激的 O-2 生成与溶酶体酶释放之间存在解离。这些发现与以下假设一致，即 PGEs 和 PGI2 对中性粒细胞刺激的抑制是细胞内环磷酸腺苷水平升高和钙依赖性事件调节的结果。此外，数据表明中性粒细胞产生 O-2 至少有两种机制，一种受 PGEs 和 PGI2 抑制，另一种独立于前列腺素调节。
