Moulin Maryline, Carpentier Stéphane, Levade Thierry, Arrigo André-Patrick
Laboratoire Stress, Chaperons et Mort cellulaire, CNRS UMR 5534, Centre de Génétique Moléculaire et Cellulaire, Université Claude Bernard, Lyon-1, 16 rue Dubois, 69622 Villeurbanne Cedex, France.
Apoptosis. 2007 Sep;12(9):1703-20. doi: 10.1007/s10495-007-0096-2.
We recently reported that a mild heat shock induces a long lasting stimulation of TRAIL-induced apoptosis of leukemic T-lymphocytes and myeloid cell lines, but not normal T-lymphocytes, which correlates with an enhanced ability of TRAIL to recognize its receptors. As shown here, this phenomenon could be inhibited by the xanthogenate agent D609, a sphingomyelin/ceramide pathway inhibitor. A caspase-dependent and D609-sensitive two-fold increase in ceramide level was elicited by heat shock plus TRAIL combined treatment. One day after heat shock, a similar increase in ceramide was induced by TRAIL. Sphingolipids/ceramides are known to regulate membrane integrity, and heat shock increases membrane fluidity. In this regard, the heat shock plus TRAIL combined treatment resulted in a D609-sensitive membrane fluidization which was far more intense than that induced by heat shock only. We also report that membrane fluidizers, that mimic the effect of heat shock, such benzyl alcohol and ethanol, potently stimulated TRAIL-induced apoptosis. As heat shock, these alcohols increased, in a D609-sensitive manner, membrane fluidity in the presence of TRAIL, the recognition of TRAIL death receptors, and ceramide levels. These results suggest that stress agents that trigger ceramide production and an overall increase in membrane fluidity are stimulators of TRAIL apoptosis.
我们最近报道，轻度热休克可诱导白血病T淋巴细胞和髓系细胞系中TRAIL诱导的凋亡受到长期刺激，但正常T淋巴细胞则不会，这与TRAIL识别其受体的能力增强相关。如下所示，这种现象可被黄原酸盐试剂D609（一种鞘磷脂/神经酰胺途径抑制剂）抑制。热休克加TRAIL联合处理可引起神经酰胺水平依赖半胱天冬酶且对D609敏感的两倍增加。热休克一天后，TRAIL可诱导类似的神经酰胺增加。已知鞘脂/神经酰胺可调节膜完整性，热休克会增加膜流动性。在这方面，热休克加TRAIL联合处理导致了对D609敏感的膜流动性增加，其强度远高于仅由热休克诱导的膜流动性增加。我们还报道，模拟热休克作用的膜流动性促进剂，如苯甲醇和乙醇，可有效刺激TRAIL诱导的凋亡。与热休克一样，这些醇类在TRAIL存在的情况下，以对D609敏感的方式增加膜流动性、TRAIL死亡受体的识别以及神经酰胺水平。这些结果表明，触发神经酰胺产生和膜流动性总体增加的应激剂是TRAIL凋亡的刺激物。
