Increased vulnerability of newly forming beta cells to cytokine-induced cell death
Increased vulnerability of newly forming beta cells to cytokine-induced cell death
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DOI：
10.1007/s00125-005-0069-3
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发表时间：
2006-01-01
期刊：
影响因子：
8.2
通讯作者：
Butler, PC
中科院分区：
文献类型：
--
作者：
Meier, JJ;Ritzel, RA;Butler, PC
目的/假设：1型糖尿病中β细胞的破坏显然是由细胞因子的释放介导的。我们质疑是否马槟榔碱诱导的细胞凋亡优先杀死复制β细胞。材料和方法：实验一，采用延时视频显微镜观察大鼠胰岛素瘤（RIN）细胞36 h。将细胞暴露于三种剂量的细胞因子混合物（最大浓度：IL-1 β 50 U/ml; TNF-α 1，000 U/ml; IFN-γ 1，000 U/ml）或媒介物，并分析总细胞数（2小时间隔）和每个细胞死亡和分裂的时间。在第二个实验中，将分离的人胰岛与相同的细胞因子混合物孵育24小时，并检查复制和配对（有丝分裂后）凋亡。结果如下：在第一个实验中，在应用细胞因子后，在下一次或随后的细胞有丝分裂后立即发生凋亡最频繁（p < 0.05）。在第二个实验中，细胞因子引起人胰岛细胞凋亡增加，有丝分裂后凋亡对的比例增加（p < 0.001）。结论/解释：细胞因子诱导的β细胞死亡优先影响新形成的β细胞，这意味着复制的β细胞可能更容易受到细胞因子的破坏。通过促进β细胞复制来扩大1型糖尿病中β细胞群的努力可能会失败，除非同时抑制了苦参碱诱导的细胞凋亡。
Aims/hypothesis: Beta cell destruction in type 1 diabetes is apparently mediated by the release of cytokines. We questioned whether cytokine-induced apoptosis preferentially kills replicating beta cells. Materials and methods: In the first experiment, rat insulinoma (RIN) cells were studied for 36 h by time-lapse video microscopy. Cells were exposed to three doses of a cytokine mixture (maximal concentration: IL-1 beta 50 U/ml; TNF-alpha 1,000 U/ml; IFN-gamma 1,000 U/ml) or vehicle and analysed for the total cell number (2-h intervals) and timing of each cell death and division. In the second experiment, isolated human islets were incubated with the same cytokine mixture for 24 h and examined for replication and paired (postmitotic) apoptosis. Results: In the first experiment, after application of cytokines, apoptosis occurred most frequently immediately after the next or subsequent cell mitosis (p < 0.05). In the second experiment, cytokines caused increased apoptosis in human islets, with an increase in the proportion of postmitotic apoptotic pairs (p < 0.001). Conclusions/interpretation: Cytokine-induced beta cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. Efforts to expand beta cell mass in type 1 diabetes by fostering beta cell replication are likely to fail unless cytokine-induced apoptosis is concurrently suppressed.