Department of Nutrition, University of Tennessee, Knoxville, Tennessee, United States of America.
PLoS One. 2011;6(7):e22485. doi: 10.1371/journal.pone.0022485. Epub 2011 Jul 29.
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.
功能性β细胞数量的减少会导致两种主要类型的糖尿病；促炎细胞因子，如白细胞介素-1β（IL-1β）和γ干扰素（γ-IFN），会激活信号通路，导致胰腺β细胞死亡和功能障碍。然而，这种情况下β细胞死亡的分子机制尚不清楚。在本报告中，我们检验了这样一个假设，即单个细胞死亡途径表现出特征性表型，可以通过在刺激特异性起始过程中发生的精确生化和代谢反应来区分它们。我们使用 832/13 和 INS-1E 大鼠胰岛素瘤细胞和分离的大鼠胰岛，提供了证据表明细胞凋亡不太可能是 IL-1β+γ-IFN 反应中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，包括：1）串联质谱法来描绘 IL-1β+γ-IFN 暴露与依托泊苷诱导的细胞凋亡之间的代谢差异，以及 2）通过药理学和分子干扰 NF-κB 活性或凋亡小体形成。这些方法在促炎细胞因子和真正的凋亡诱导剂引发的细胞死亡途径之间提供了明确的区分。总的来说，本文报告的结果表明，胰腺β细胞在受到喜树碱或 staurosporine 时会发生细胞凋亡，但不会受到促炎细胞因子的影响。
