The regulation of the mitochondrial apoptotic pathway by glucocorticoid receptor in collaboration with Bcl-2 family proteins in developing T cells.
The regulation of the mitochondrial apoptotic pathway by glucocorticoid receptor in collaboration with Bcl-2 family proteins in developing T cells.
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DOI：
10.1007/s10495-016-1320-8
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Berki T
中科院分区：
文献类型：
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作者：
Prenek L;Boldizsár F;Kugyelka R;Ugor E;Berta G;Németh P;Berki T
糖皮质激素（GC）在调节CD 4 + CD 8+双阳性（DP）胸腺细胞的选择和凋亡方面非常重要。DP胸腺细胞的显着的GC敏感性，观察到较早，可能是由于经典的（基因组）和替代（非基因组）糖皮质激素受体（GR）信号转导事件的组合，修改激活或凋亡途径。特别是，先前证明的线粒体易位激活GR在DP胸腺细胞提供了一个迷人的解释，其显着的GC诱导的细胞凋亡的敏感性。然而，GR的线粒体易位如何调节细胞凋亡的精细分子细节仍不清楚。因此，在本研究中，我们打算检查哪些凋亡途径可能参与GC诱导的胸腺细胞凋亡。此外，我们研究了GR和Bcl-2蛋白之间的潜在关系。使用体外试验系统，用GC类似物地塞米松（DX）处理4周龄BALB/c小鼠的胸腺细胞。DX处理后，Bax在线粒体中积累。线粒体GR与Bcl-2家族成员：巴克、Bim、Bcl-xL相关。DX处理后，胸腺细胞中检测到细胞色素C和活性半胱天冬酶-3，8和9水平升高。这些结果支持了这一假设，即在GC诱导的胸腺细胞凋亡的早期阶段，线粒体途径起着至关重要的作用，细胞色素C的释放和caspase-9的激活证实。caspase-8的激活可能是由于凋亡信号通路之间的串扰。我们认为GC诱导的Bax在线粒体内的积累以及GR与Bim、Bcl-xL和巴克之间的相互作用可能在胸腺细胞凋亡的调节中起作用。
Glucocorticoids (GC) are important in the regulation of selection and apoptosis of CD4+CD8+ double-positive (DP) thymocytes. The pronounced GC-sensitivity of DP thymocytes, observed earlier, might be due to the combination of classical (genomic) and alternative (non-genomic) glucocorticoid receptor (GR) signaling events modifying activation or apoptotic pathways. In particular, the previously demonstrated mitochondrial translocation of activated GR in DP thymocytes offered a fascinating explanation for their pronounced GC-induced apoptosis sensitivity. However, the fine molecular details how the mitochondrial translocation of GR might regulate apoptosis remained unclear. Therefore, in the present study, we intended to examine which apoptotic pathways could be involved in GC-induced thymocyte apoptosis. Furthermore we investigated the potential relationship between the GR and Bcl-2 proteins. Using an in vitro test system, thymocytes from 4-week-old BALB/c mice, were treated with the GC-analogue dexamethasone (DX). Bax accumulated in mitochondria upon DX treatment. Mitochondrial GR showed association with members of the Bcl-2 family: Bak, Bim, Bcl-xL. Elevated Cytochrome C, and active caspase-3, -8, and -9 levels were detected in thymocytes after DX treatment. These results support the hypothesis that in early phases of GC-induced thymocyte apoptosis, the mitochondrial pathway plays a crucial role, confirmed by the release of Cytochrome C and the activation of caspase-9. The activation of caspase-8 was presumably due to cross-talk between apoptotic signaling pathways. We propose that the GC-induced mitochondrial accumulation of Bax and the interaction between the GR and Bim, Bcl-xL and Bak could play a role in the regulation of thymocyte apoptosis.