LIGHT/IFN-γ triggers β cells apoptosis via NF-κB/Bcl2-dependent mitochondrial pathway.
LIGHT/IFN-γ triggers β cells apoptosis via NF-κB/Bcl2-dependent mitochondrial pathway.
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LIGHT/IFN-gamma 通过 NF-kappa B/Bcl2 依赖性线粒体途径触发 β 细胞凋亡
DOI：
10.1111/jcmm.12876
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发表时间：
2016-10
影响因子：
5.3
通讯作者：
Zhang KQ
中科院分区：
文献类型：
--
作者：
Zheng QY;Cao ZH;Hu XB;Li GQ;Dong SF;Xu GL;Zhang KQ
LIGHT在糖尿病发病时招募并激活胰岛中的幼稚T细胞。活化的T淋巴细胞分泌的IFN-γ参与β细胞凋亡。然而，LIGHT是否使IFNγ诱导的β细胞破坏敏感仍不清楚。在这项研究中，我们使用鼠β细胞系MIN 6和原代胰岛细胞作为模型，用于研究参与LIGHT/IFNγ诱导的胰腺β细胞破坏的潜在细胞机制。LIGHT和IFN-γ协同降低MIN 6和原代胰岛细胞活力;细胞活力降低是由于细胞凋亡，如通过流式细胞术检测的膜联蛋白V+细胞百分比的显著增加所证明的。除了细胞色素c释放和NF-κB活化的显著增加外，LIGHT和IFN-γ的组合还导致MIN 6细胞中抗凋亡蛋白Bcl-2和Bcl-xL的表达明显降低，但促凋亡蛋白巴克和Bax的表达增加。因此，LIGHT缺乏导致NF-κB活化和巴克表达减少，以及非肥胖糖尿病小鼠的胰岛炎。用特异性NF-κB抑制剂PDTC（吡咯烷二硫代氨基甲酸酯）抑制NF-κB活化，逆转了Bcl-xL下调和Bax上调，并导致LIGHT和IFN-γ处理的细胞活力显著增加。此外，在LIGHT和IFN-γ处理后观察到裂解的半胱天冬酶-9、-3和PARP（聚（ADP-核糖）聚合酶）。caspase抑制剂预处理显著减弱LIGHT和IFNγ诱导的细胞凋亡。综上所述，我们的结果表明，LIGHT信号通路与IFN-γ结合通过NF-κB/Bcl 2依赖性线粒体通路诱导β细胞凋亡。
LIGHT recruits and activates naive T cells in the islets at the onset of diabetes. IFN‐γ secreted by activated T lymphocytes is involved in beta cell apoptosis. However, whether LIGHT sensitizes IFNγ‐induced beta cells destruction remains unclear. In this study, we used the murine beta cell line MIN6 and primary islet cells as models for investigating the underlying cellular mechanisms involved in LIGHT/IFNγ – induced pancreatic beta cell destruction. LIGHT and IFN‐γ synergistically reduced MIN6 and primary islet cells viability; decreased cell viability was due to apoptosis, as demonstrated by a significant increase in Annexin V+ cell percentage, detected by flow cytometry. In addition to marked increases in cytochrome c release and NF‐κB activation, the combination of LIGHT and IFN‐γ caused an obvious decrease in expression of the anti‐apoptotic proteins Bcl‐2 and Bcl‐xL, but an increase in expression of the pro‐apoptotic proteins Bak and Bax in MIN6 cells. Accordingly, LIGHT deficiency led to a decrease in NF‐κB activation and Bak expression, and peri‐insulitis in non‐obese diabetes mice. Inhibition of NF‐κB activation with the specific NF‐κB inhibitor, PDTC (pyrrolidine dithiocarbamate), reversed Bcl‐xL down‐regulation and Bax up‐regulation, and led to a significant increase in LIGHT‐ and IFN‐γ‐treated cell viability. Moreover, cleaved caspase‐9, ‐3, and PARP (poly (ADP‐ribose) polymerase) were observed after LIGHT and IFN‐γ treatment. Pretreatment with caspase inhibitors remarkably attenuated LIGHT‐ and IFNγ‐induced cell apoptosis. Taken together, our results indicate that LIGHT signalling pathway combined with IFN‐γ induces beta cells apoptosis via an NF‐κB/Bcl2‐dependent mitochondrial pathway.
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影响因子：
3.7
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Cao ZH;Zheng QY;Li GQ;Hu XB;Feng SL;Xu GL;Zhang KQ
通讯作者：
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