Baratelli Felicita, Krysan Kostyantyn, Heuzé-Vourc'h Nathalie, Zhu Li, Escuadro Brian, Sharma Sherven, Reckamp Karen, Dohadwala Mariam, Dubinett Steven M
Jonsson Comprehensive Cancer Center and Division of Pulmonary and Critical Care Medicine, UCLA Geffen School of Medicine, 37-131 CHS, 10833 Le Conte Ave., Room 37-131 CHS, Los Angeles, CA 90095, USA.
J Leukoc Biol. 2005 Aug;78(2):555-64. doi: 10.1189/jlb.1004569. Epub 2005 May 20.
Control of apoptosis is fundamental for dendritic cell (DC) homeostasis. Numerous factors maintain DC viability throughout their lifespan, including inhibitor of apoptosis proteins. Among them, survivin is overexpressed in many human malignancies, but its physiological function in normal cells has not been fully delineated. Prostaglandin E2 (PGE2), also overproduced in several malignancies, has shown to induce proapoptotic and antiapoptotic effects in different cell types, including immune cells. In DC, PGE2 predominantly affects maturation and modulates immune functions. Here, we show that exposure of monocyte-derived DC to PGE2 (10(-5) M) for 72 h significantly increased DC survivin mRNA and protein expression. In contrast, DC, matured with lipopolysaccharide or tumor necrosis factor alpha, did not reveal survivin induction in response to PGE2. Following exposure to apoptotic stimuli, DC treated with PGE2 exhibited an overall increased viability compared with control DC, and this effect was correlated inversely with caspase-3 activation. Moreover, PGE2-treated, survivin-deficient DC demonstrated reduced viability in response to apoptotic stimuli. Further analysis indicated that PGE2 induced DC survivin expression in an E prostanoid (EP)2/EP4 receptor and phosphatidylinositol-3 kinase-dependent manner. These findings suggest that PGE2-dependent regulation of survivin is important in modulating apoptosis resistance in human DC.
细胞凋亡的调控对于树突状细胞（DC）的稳态至关重要。众多因素在DC的整个生命周期中维持其活力，包括凋亡抑制蛋白。其中，生存素在许多人类恶性肿瘤中过度表达，但其在正常细胞中的生理功能尚未完全阐明。前列腺素E2（PGE2）在几种恶性肿瘤中也过度产生，已显示在包括免疫细胞在内的不同细胞类型中诱导促凋亡和抗凋亡作用。在DC中，PGE2主要影响成熟并调节免疫功能。在此，我们表明，将单核细胞衍生的DC暴露于PGE2（10^(-5) M）72小时可显著增加DC生存素mRNA和蛋白表达。相比之下，用脂多糖或肿瘤坏死因子α成熟的DC对PGE2无生存素诱导反应。暴露于凋亡刺激后，与对照DC相比，用PGE2处理的DC总体活力增加，且这种作用与半胱天冬酶-3激活呈负相关。此外，用PGE2处理的生存素缺陷型DC对凋亡刺激的反应显示活力降低。进一步分析表明，PGE2以E前列腺素（EP）2/EP4受体和磷脂酰肌醇-3激酶依赖性方式诱导DC生存素表达。这些发现表明，PGE2依赖性生存素调节在调节人DC的凋亡抗性中很重要。
