Dexamethasone-induced thymocyte apoptosis: Apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases
Dexamethasone-induced thymocyte apoptosis: Apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases
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DOI：
10.1182/blood.v93.7.2282.407a23_2282_2296
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发表时间：
1999-04-01
期刊：
影响因子：
20.3
通讯作者：
Riccardi, C
中科院分区：
文献类型：
--
作者：
Cifone, MG;Migliorati, G;Riccardi, C
糖皮质激素(GCH)被认为是T淋巴细胞生长和分化的调节剂，尤其是有报道称GCH可以诱导胸腺细胞的凋亡。然而，导致GCH死亡的分子机制尚不清楚。本工作分析了合成的GCH地塞米松(Dex)诱导正常小鼠胸腺细胞凋亡的相关生化事件。结果表明，地塞米松诱导的胸腺细胞凋亡可归因于酸性鞘磷脂酶(ASMase)的激活导致神经酰胺的早期生成。Caspase活性在地塞米松诱导的细胞凋亡中起关键作用，位于aSMase活性的下游，因为抑制早期神经酰胺的生成会抑制Caspase的激活和胸腺细胞的死亡。此外，地塞米松通过蛋白激酶C(PKC)和G蛋白依赖的磷脂酰肌醇特异性磷脂酶C(PI-PLC)快速诱导二酰甘油(DAG)的产生，这一事件发生在SMase激活之前，也是激活SMase所必需的。事实上，U73122抑制PI-PLC可以完全阻止地塞米松诱导的aSMase活性、神经酰胺的产生，从而阻止caspase的激活和凋亡。所有这些效应都需要地塞米松与GCH受体(GR)的相互作用，被GR拮抗剂RU486拮抗，并先于GCH/GR激活的转录和蛋白质合成，这些观察表明GCH通过一条复杂的信号通路激活胸腺细胞死亡，这需要不同的生化事件的顺序激活。(C)1999年由美国血液病学会主办。
Glucocorticoid hormones (GCH) have been implicated as regulators of T-lymphocyte growth and differentiation, In particular, it has been reported that GCH can induce thymocyte apoptosis. However, the molecular mechanisms responsible for this GCH-induced death have not been clarified. In this work, the biochemical events associated with apoptosis induced by Dexamethasone (Dex), a synthetic GCH, in normal mouse thymocytes, have been analyzed. Results indicate that Dex-induced thymocyte apoptosis is attributable to an early ceramide generation caused by the activation of an acidic sphingomyelinase (aSMase). Caspase activity plays a crucial role in Dex-induced apoptosis and is downstream the aSMase activation in that inhibition of the early ceramide generation inhibits caspase activation and thymocyte death. Moreover, Dex treatment rapidly induces diacylglycerol (DAG) generation, through a protein kinase C (PKC) and G-protein-dependent phosphatidylinositol-specific phospholipase C (PI-PLC), an event which precedes and is required for aSMase activation. Indeed, PI-PLC inhibition by U73122 totally prevents Dex-induced aSMase activity, ceramide generation, and consequently, caspase activation and apoptosis. All these effects require Dex interaction with GCH receptor (GR), are countered by the GR antagonist RU486, and precede the GCH/GR-activated transcription and protein synthesis, These observations indicate that GCH activates thymocyte death through a complex signaling pathway that requires the sequential activation of different biochemical events. (C) 1999 by The American Society of Hematology.