Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-κB activation
Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-κB activation
复制标题
DOI：
10.1016/j.bbrc.2012.01.130
复制
发表时间：
2012-02-24
影响因子：
3.1
通讯作者：
Welsh, Nils
中科院分区：
文献类型：
--
作者：
Hindlycke, Henrietta;Lu, Tao;Welsh, Nils
对胰岛素产生β细胞的研究已经报道了对NF-κ B活化的矛盾反应，包括促凋亡和抗凋亡作用，可能反映了来自不同物种的β细胞的使用。因此，本研究的目的是比较大鼠和人胰岛素产生细胞中NF-κ B的时间激活，并将其与细胞死亡、STAT-1激活和一氧化氮（NO）产生的动力学相关。将大鼠RIN 5AH和人胰岛细胞暴露于细胞因子IL-1 β和IFN-γ以及NOS抑制剂氨基胍。在不同时间点分析细胞死亡、NO产生、I κ B α磷酸化、p65甲基化、STAT-1磷酸化和cIAP-2水平。细胞因子诱导的RIN 5 AH细胞死亡发生在第1天，这是由NF-κ B激活，STAT-1磷酸化和NO的产生所阻止的。另一方面，人胰岛细胞在第3天和第5天通过NO非依赖性机制死亡。这种后来发生的细胞死亡与I κ B α磷酸化和p65甲基化的逐渐减少以及NF-κ B靶基因Mkt和cIAP-2的表达降低有关。STAT-1磷酸化在人胰岛细胞中的整个细胞因子暴露期间持续高。结果支持NF-κ B的促存活作用和STAT-1在人胰岛细胞中的促凋亡作用。因此，啮齿类动物胰岛素产生细胞可能不适合作为马槟榔碱诱导的损伤背景下的人β-细胞的模型。(C)2012 Elsevier Inc. All rights reserved.
Studies of insulin producing beta-cells have reported conflicting responses to NF-kappa B activation, encompassing both pro- and anti-apoptotic effects, possibly reflecting the use of beta-cells from different species. Therefore, the aim of this study was to compare the temporal activation of NF-kappa B in rat and human insulin producing cells and relate this to the dynamics of cell death, STAT-1 activation and the production of nitric oxide (NO). Rat RIN5AH and human islet cells were exposed to the cytokines IL-1 beta and IFN-gamma and the NOS inhibitor aminoguanidine. Cell death, NO production, I kappa B alpha phosphorylation, p65 methylation, STAT-1 phosphorylation and cIAP-2 levels were analyzed at different time-points. Cytokine-induced RIN5AH cell death occurred on day 1, and this was paralleled by NF-kappa B activation, STAT-1 phosphorylation and production of NO. On the other hand, the human islet cells instead died by an NO-independent mechanism on day 3 and 5. This later occurring cell death was associated with a gradual decrease in I kappa B alpha phosphorylation and p65 methylation, and a lowered expression of the NF-kappa B target genes Mkt and cIAP-2. STAT-1 phosphorylation was persistently high during the entire cytokine exposure period in human islet cells. The results favor a pro-survival role of NF-kappa B and a pro-apoptotic role of STAT-1 in human islet cells. Thus, rodent insulin producing cells may not be suitable as models for human beta-cells in the context of cytokine-induced damage. (C) 2012 Elsevier Inc. All rights reserved.