Role of calcium in pancreatic islet cell death by IFN-γ/TNF-α
Role of calcium in pancreatic islet cell death by IFN-γ/TNF-α
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DOI：
10.4049/jimmunol.172.11.7008
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Lee, MS
中科院分区：
文献类型：
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作者：
Chang, I;Cho, NJ;Lee, MS
我们通过IFN-γ/TNF-α协同作用研究了与胰腺β细胞凋亡相关的细胞内事件。IFN-γ/TNF-α治疗MIN 6 N8胰岛素瘤细胞增加了高电压激活的Ca 2+电流的幅度，而单独使用IFN-γ或TNF-α治疗则没有。IFN-γ/TNF-α处理也增加了胞浆Ca 2+浓度（[Ca 2 +]（c））。硝苯地平阻断L-型Ca ~（2+）通道可消除IFN-γ/TNF-α引起的胰岛素瘤细胞死亡。二氮嗪可减弱电压激活的钙电流，抑制IFN-γ/TNF-α引起的MIN 6 N8细胞死亡，而格列本脲可增强电压激活的钙电流，增强胰岛素瘤细胞死亡。蛋白激酶C抑制剂减弱了MIN 6 N8细胞死亡和IFN-γ/TNF-α引起的[Ca 2 +]（c）增加。随着[Ca 2 +]（c）的增加，钙蛋白酶被激活，钙蛋白酶抑制剂减少了IFN-γ/TNF-α引起的胰岛素瘤细胞死亡。作为钙蛋白酶的下游，钙调神经磷酸酶被激活，FK 506对钙调神经磷酸酶激活的抑制减少了IFN-γ/TNF-α引起的胰岛素瘤细胞死亡。BAD磷酸化被IFN-γ/TNF-α降低，因为钙调磷酸酶活性增加，这被FK 506逆转。IFN-γ/TNF-α诱导细胞色素c从线粒体易位到细胞质并激活caspase-9。效应物半胱天冬酶如半胱天冬酶-3或-7也被IFN-γ/TNF-α处理激活。这些结果表明，IFN-γ/TNF-α协同作用通过Ca 2+通道激活诱导胰腺β细胞凋亡，随后是下游细胞内事件，如线粒体事件和半胱天冬酶激活，并且还表明Ca 2+调节在1型糖尿病中的治疗潜力。
We studied the intracellular events associated with pancreatic beta cell apoptosis by IFN-gamma/TNF-alpha synergism. IFN-gamma/TNF-alpha treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca2+ currents, while treatment with IFN-gamma or TNF-alpha alone did not. Cytosolic Ca2+ concentration ([Ca2+](c)) was also increased by IFN-gamma/TNF-alpha treatment. Blockade of L-type Ca2+ channel by nifedipine abrogated death of insulinoma cells by IFN-gamma/TNF-alpha. Diazoxide that attenuates voltage-activated Ca2+ currents inhibited MIN6N8 cell death by IFN-gamma/TNF-alpha, while glibenclamide that accentuates voltage-activated Ca2+ currents augmented insulinoma cell death. A protein kinase C inhibitor attenuated MIN6N8 cell death and the increase in [Ca2+](c) by IFN-gamma/TNF-alpha. Following the increase in [Ca2+](c), calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-gamma/TNF-alpha. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-gamma/TNF-alpha. BAD phosphorylation was decreased by IFN-gamma/TNF-alpha because of the increased calcineurin activity, which was reversed by FK506. IFN-gamma/TNF-alpha induced cytochrome c translocation from mitochondria to cytoplasm and activation of caspase-9. Effector caspases such as caspase-3 or -7 were also activated by IFN-gamma/TNF-alpha treatment. These results indicate that IFN-gamma/TNF-alpha synergism induces pancreatic beta cell apoptosis by Ca2+ channel activation followed by downstream intracellular events such as mitochondrial events and caspase activation and also suggest the therapeutic potential of Ca2+ modulation in type 1 diabetes.