Spatafora M, Chiappara G, D'Amico D, Volpes D, Melis M, Pace E, Merendino A
Consiglio Nazionale delle Ricerche, Università di Palermo, Italy.
Pharmacol Res. 1991 Apr;23(3):247-57. doi: 10.1016/s1043-6618(05)80084-2.
In this investigation we have examined the effects of indomethacin, an inhibitor of the cyclooxygenase pathway of arachidonic acid, upon the kinetics of the release of tumour necrosis factor alpha (TNF) and of the expression of TNF gene by lipopolysaccharide (LPS)-stimulated human blood monocytes (BM). Following stimulation of BM with LPS, TNF was released within 2 h, reached peak values at 8 h and declined at subsequent time-points (24 and 48 h). Indomethacin (10(-5) M) slightly stimulated the production of TNF at 2, 4, and 8 h and prevented the decline of TNF observed at 24 and 48 h. This effect was related to the persistence of TNF synthesis, as demonstrated by kinetic evaluation of the expression of TNF gene performed by dot-blot analysis. The effects of indomethacin on TNF release and TNF gene expression were due to the inhibition of endogenous prostaglandin (PG)E2 production. In the absence of indomethacin, PGE2 release by the LPS-stimulated BM began concomitantly with the decline of TNF production by the same cells under the same stimulus. Indomethacin completely blocked PGE2 release at any time-point. Exogenous PGE2 suppressed the release of TNF and the expression of TNF gene in a dose-dependent fashion. Exogenous PGE2 completely reversed the effects of indomethacin on TNF production at 24 h. These findings suggest that indomethacin may significantly alter the kinetics of TNF release and TNF gene expression by LPS-stimulated BM. These effects are related, at least in part, to the inhibition of the production of endogenous PGE2, an important self-driven regulatory factor of the kinetics of TNF production.
在本研究中，我们检测了花生四烯酸环氧化酶途径抑制剂吲哚美辛对脂多糖（LPS）刺激的人血单核细胞（BM）释放肿瘤坏死因子α（TNF）的动力学及TNF基因表达的影响。用LPS刺激BM后，TNF在2小时内释放，8小时达到峰值，随后在24小时和48小时下降。吲哚美辛（10⁻⁵M）在2、4和8小时轻微刺激TNF的产生，并阻止了在24小时和48小时观察到的TNF下降。通过斑点印迹分析对TNF基因表达进行动力学评估表明，这种作用与TNF合成的持续存在有关。吲哚美辛对TNF释放和TNF基因表达的影响是由于对内源性前列腺素（PG）E2产生的抑制。在没有吲哚美辛的情况下，LPS刺激的BM释放PGE2与相同刺激下相同细胞产生的TNF下降同时开始。吲哚美辛在任何时间点都完全阻断PGE2的释放。外源性PGE2以剂量依赖性方式抑制TNF的释放和TNF基因的表达。外源性PGE2在24小时完全逆转了吲哚美辛对TNF产生的影响。这些发现表明，吲哚美辛可能显著改变LPS刺激的BM释放TNF的动力学及TNF基因表达。这些作用至少部分与抑制内源性PGE2的产生有关，内源性PGE2是TNF产生动力学的重要自我驱动调节因子。
