IL-1β induces ER stress in a JNK dependent manner that determines cell death in human pancreatic epithelial MIA PaCa-2 cells
IL-1β induces ER stress in a JNK dependent manner that determines cell death in human pancreatic epithelial MIA PaCa-2 cells
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DOI：
10.1007/s10495-010-0498-4
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发表时间：
2010-07-01
期刊：
影响因子：
7.2
通讯作者：
Datta, Malabika
中科院分区：
文献类型：
--
作者：
Verma, Gaurav;Datta, Malabika
促炎细胞因子IL-1 β（白细胞介素-1 β）是胰腺细胞凋亡和细胞死亡的重要决定因素，胰腺细胞凋亡和细胞死亡是糖尿病期间的常见特征。使用人源性胰腺MIA PaCa-2细胞，我们描述了这一观察背后的潜在分子机制之一。将这些细胞与IL-1 β以0.5 - 3.0 ng/ml的剂量孵育，在36 h时引起显著的细胞死亡。这伴随着JNK和p38磷酸化的显著增加以及内质网（ER）应激标志物（即BiP、CHOP、GADD 34、ATF 4和sXBP 1）水平的增加。IL-1 β还导致eIF 2 α磷酸化增加，所有这些事件都可以通过JNK抑制剂SP 600125预处理来预防。时程研究表明，虽然IL-1 β介导的JNK磷酸化早在IL-1 β处理2小时就被诱导，但ER应激标志物的诱导在稍后的时间点是明显的。甚至在ER应激抑制剂4-苯基丁酸酯存在下也观察到IL-1 β刺激的JNK磷酸化，并且在JNK抑制剂存在下显著防止了细胞活力的降低。所有这些表明JNK激活是ER应激诱导和细胞死亡的先决条件。迄今为止的报道一致地证明JNK活化是胰腺中IL-1 β诱导ER应激的结果。我们在这里首次表明，IL-1 β激活JNK是随后诱导ER应激和细胞死亡的前奏。因此，这些表明JNK-ER应激轴在决定MIA PaCa-2细胞中IL-1 β降低的存活状态中是关键的。
The proinflammatory cytokine, IL-1 beta (Interleukin-1 beta) is a significant determinant of pancreatic apoptosis and cell death that are common characteristics during diabetes. Using human derived pancreatic MIA PaCa-2 cells, we describe one of the underlying molecular mechanisms behind this observation. Incubation of these cells with IL-1 beta at doses from 0.5 to 3.0 ng/ml caused significant cell death at 36 h. This was accompanied with marked increases in JNK and p38 phosphorylation together with increased levels of the endoplasmic reticulum (ER) stress markers, namely BiP, CHOP, GADD34, ATF4 and sXBP1. IL-1 beta also led to increased phosphorylation of eIF2 alpha and all these events could be prevented by pretreatment with the JNK inhibitor, SP600125. A time course study indicated that while IL-1 beta mediated JNK phosphorylation was induced as early as 2 h of IL-1 beta treatment, induction of the ER stress markers was evident at later time points. IL-1 beta stimulated JNK phosphorylation was observed even in the presence of the ER stress inhibitor, 4-phenyl butyrate and the decrease in cell viability was significantly prevented in the presence of the JNK inhibitor. All these suggest that JNK activation is a pre-requisite for ER stress induction and cell death. Reports till date have consistently demonstrated JNK activation as a consequence of ER stress induction by IL-1 beta in the pancreas. We show here for the first time that the activation of JNK by IL-1 beta is a prelude to the subsequent induction of ER stress and cell death. These therefore suggest that the JNK-ER stress axis is critical in deciding the decreased survival status by IL-1 beta in MIA PaCa-2 cells.