Kaurane diterpenes protect against apoptosis and inhibition of phagocytosis in activated macrophages
Kaurane diterpenes protect against apoptosis and inhibition of phagocytosis in activated macrophages
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DOI：
10.1038/sj.bjp.0707382
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发表时间：
2007-09-01
影响因子：
7.3
通讯作者：
Bosca, L.
中科院分区：
文献类型：
--
作者：
de las Heras, B.;Hortelano, S.;Bosca, L.
背景和目的：贝壳杉烷二萜叶醇和线性醇是核因子 kappa B 激活的抑制剂，核因子 kappa B 是一种参与炎症反应的转录因子。已在培养的腹膜巨噬细胞和小鼠巨噬细胞系 RAW 264.7 中分析了这些二萜对细胞凋亡和吞噬作用的影响。实验方法：将巨噬细胞维持在培养物中，并在不存在或存在二萜的情况下用促炎刺激物激活。确定了这些条件下这些细胞的细胞凋亡和吞噬作用。 主要结果：巨噬细胞与细菌脂多糖 (LPS)/干扰素-γ (IFN-γ) 混合物一起孵育，通过 NO 依赖性途径诱导细胞凋亡，这种作用被低 μM 范围的叶醇和线性醇显着抑制，但没有细胞毒性作用。 NO 供体诱导的巨噬细胞凋亡也受到抑制。二萜通过与抑制 caspase-3 激活、细胞色素 c 释放到胞浆和 p53 过度表达以及改变 Bcl-2 家族蛋白水平（特别是 Bax 水平）相容的机制来防止细胞凋亡。这些二萜减少了聚（ADP-核糖）聚合酶（一种成熟的半胱天冬酶底物）的裂解。用叶醇和线性醇处理细胞可减少 RAW 264.7 细胞对酵母聚糖生物颗粒的吞噬作用，并在更大程度上减少腹膜巨噬细胞对酵母聚糖生物颗粒的吞噬作用。结论和意义：两种二萜均可保护巨噬细胞免于凋亡并抑制吞噬作用，从而导致巨噬细胞功能的矛盾控制，因为活力延长，但炎症和吞噬功能受损。
Background and purpose: The kaurane diterpenes foliol and linearol are inhibitors of the activation of nuclear factor kappa B, a transcription factor involved in the inflammatory response. Effects of these diterpenes on apoptosis and phagocytosis have been analysed in cultured peritoneal macrophages and in the mouse macrophage cell line, RAW 264.7.Experimental approach: Macrophages were maintained in culture and activated with pro-inflammatory stimuli in the absence or presence of diterpenes. Apoptosis and the phagocytosis in these cells under these conditions were determined.Key results: Incubation of macrophages with a mixture of bacterial lipopolysaccharide ( LPS)/interferon-gamma ( IFN-gamma) induced apoptosis through a NO-dependent pathway, an effect significantly inhibited by foliol and linearol in the low mu M range, without cytotoxic effects. Apoptosis in macrophages induced by NO donors was also inhibited. The diterpenes prevented apoptosis through a mechanism compatible with the inhibition of caspase-3 activation, release of cytochrome c to the cytosol and p53 overexpression, as well as an alteration in the levels of proteins of the Bcl-2 family, in particular, the levels of Bax. Cleavage of poly( ADP-ribose) polymerase, a well-established caspase substrate, was reduced by these diterpenes. Treatment of cells with foliol and linearol decreased phagocytosis of zymosan bioparticles by RAW 264.7 cells and to a greater extent by peritoneal macrophages.Conclusions and implications: Both diterpenes protected macrophages from apoptosis and inhibited phagocytosis, resulting in a paradoxical control of macrophage function, as viability was prolonged but inflammatory and phagocytic functions were impaired.