Modulation of pro- and antiapoptotic molecules in double-positive (CD4+ CD8+) thymocytes following dexamethasone treatment
Modulation of pro- and antiapoptotic molecules in double-positive (CD4+ CD8+) thymocytes following dexamethasone treatment
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DOI：
10.1124/jpet.106.108480
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发表时间：
2006-11-01
影响因子：
3.5
通讯作者：
Riccardi, Carlo
中科院分区：
文献类型：
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作者：
Bianchini, Rodolfo;Nocentini, Giuseppe;Riccardi, Carlo
糖皮质激素在调节T淋巴细胞的动态平衡和发育中起着重要作用。特别是，糖皮质激素治疗可诱导CD4(+)CD8(+)双阳性(DP)胸腺细胞大量凋亡。这种作用机制是多方面的，主要由基因转录调控所驱动。为了找出哪些基因受到调控，我们通过全球基因表达谱分析了地塞米松(一种合成的糖皮质激素)处理3h的DP胸腺细胞。结果表明163个基因被调控，这也被核糖核酸酶保护实验或实时聚合酶链式反应所证实。特别是，地塞米松引起促进DP胸腺细胞存活的基因(例如，Notch1，细胞因子信号抑制物1，DNA结合抑制物3)的下调，或通过神经酰胺途径(UDP-葡萄糖神经酰胺葡萄糖基转移酶，鞘氨醇1-磷酸磷酸酶，二氢神经酰胺去饱和酶，异构体1，G蛋白偶联受体65)或通过线粒体机制调节激活细胞死亡的基因。在后者中，有参与控制氧化还原状态的基因(硫氧还蛋白还原酶、硫氧还蛋白还原酶抑制因子和NADP(+)依赖的异柠檬酸脱氢酶)和Tis11家族的基因，这些基因包括Bim、BFL-1、Bclxl和Bclxβ。我们的研究表明，地塞米松处理的DP胸腺细胞调节了一些属于凋亡相关系统的基因，这些基因可以促进胸腺细胞的凋亡。
Glucocorticoids play a role in regulation of T lymphocytes homeostasis and development. In particular, glucocorticoid treatment induces massive apoptosis of CD4(+)CD8(+) double-positive (DP) thymocytes. This effect is due to many mechanisms, mainly driven by modulation of gene transcription. To find out which genes are modulated, we analyzed DP thymocytes treated for 3 h with dexamethasone (a synthetic glucocorticoid) by global gene expression profiling. Results indicate modulation of 163 genes, also confirmed by either RNase protection assay or real-time polymerase chain reaction. In particular, dexamethasone caused down-regulation of genes promoting DP thymocyte survival (e.g., Notch1, suppressor of cytokine signaling 1, and inhibitor of DNA binding 3) or modulation of genes activating cell death through the ceramide pathway (UDP-glucose ceramide glucosyltransferase, sphingosine 1-phosphate phosphatase, dihydroceramide desaturase, isoform 1, and G protein-coupled receptor 65) or through the mitochondrial machinery. Among the latter, there are Bcl-2 family members (Bim, Bfl-1, Bcl-xL, and Bcl-x beta), genes involved in the control of redox status (thioredoxin reductase, thioredoxin reductase inhibitor, and NADP(+)-dependent isocitrate dehydrogenase) and genes belonging to Tis11 family that are involved in mRNA stability. Our study suggests that dexamethasone treatment of DP thymocytes modulates several genes belonging to apoptosis-related systems that can contribute to their apoptosis.