Pancreatic β-cell death in response to pro-inflammatory cytokines is distinct from genuine apoptosis.
Pancreatic β-cell death in response to pro-inflammatory cytokines is distinct from genuine apoptosis.
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胰腺β细胞对促炎细胞因子的反应性死亡不同于真正的细胞凋亡。
DOI：
10.1371/journal.pone.0022485
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Campagna SR
中科院分区：
文献类型：
--
作者：
Collier JJ;Burke SJ;Eisenhauer ME;Lu D;Sapp RC;Frydman CJ;Campagna SR
功能性β细胞质量的减少导致两种主要形式的糖尿病;促炎细胞因子，如白细胞介素-1 β（IL-1β）和γ-干扰素（γ-IFN），激活直接胰腺β细胞死亡和功能障碍的信号通路。然而，在这种情况下，β细胞死亡的分子机制还没有得到很好的理解。在这份报告中，我们测试的假设，个别细胞死亡途径显示特征表型，使他们能够区分的精确的生化和代谢反应，发生在刺激特异性启动。使用832/13和INS-1 E大鼠胰岛素瘤细胞和分离的大鼠胰岛，我们提供的证据表明，细胞凋亡不太可能是响应IL-1β+γ-IFN的β细胞死亡的主要途径。这一结论是通过几种不同的跨学科策略的实验结果得出的，这些策略包括：1）串联质谱法，以描绘IL-1β+γ-IFN暴露与喜树碱诱导凋亡之间的代谢差异; 2）对NF-κB活性或凋亡小体形成的药理学和分子干扰。这些方法在由促炎细胞因子和真正的细胞凋亡诱导剂引发的细胞死亡途径中提供了明确的区别。总的来说，本文报道的结果证明胰腺β细胞响应于喜树碱或星形孢菌素而非促炎性细胞因子而经历凋亡。
A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines.
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