PGJ2-stimulated β-cell apoptosis is associated with prolonged UPR activation
PGJ2-stimulated β-cell apoptosis is associated with prolonged UPR activation
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DOI：
10.1152/ajpendo.00274.2006
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发表时间：
2007-04-01
影响因子：
5.1
通讯作者：
Corbett, John A.
中科院分区：
文献类型：
--
作者：
Chambers, Kari T.;Weber, Sarah M.;Corbett, John A.
PGJ(2) 刺激的 β 细胞凋亡与延长 UPR 激活有关。 Am J Physiol Endocrinol Metab 292：E1052-E1061，2007。首次发表于 2006 年 12 月 5 日； doi：10.1152/ajpendo.00274.2006。 - 过氧化物酶体增殖物激活受体-γ (PPARγ) 配体已被证明具有抗炎特性，包括抑制转录因子激活和炎症基因的表达。使用胰腺 β 细胞，我们发现 PPAR γ 配体（例如 15-脱氧-Delta(12,14)-前列腺素 J(2) (PGJ(2))）可通过相关途径减弱干扰素 γ 诱导的信号转导器和转录激活剂 1 的激活以及白细胞介素 (IL)-1 β 诱导的核因子 kappa B 的激活 内质网应激和未折叠蛋白反应（UPR）的诱导。 UPR 是由许多细胞应激源激活的保守细胞反应，被认为可以减轻应激并促进细胞存活。然而，UPR 的延长激活会导致细胞凋亡。在本报告中，我们研究了 PGJ(2) 对 UPR 激活的影响以及这种激活对细胞存活的影响。与细胞死亡途径的诱导一致，用 PGJ(2) 处理大鼠胰岛和 RINm5F 细胞 24 小时会导致 caspase-3 激活和 caspase 依赖性 β 细胞死亡。这些配体的作用似乎对 β 细胞没有选择性，因为 PGJ(2) 以类似的方式刺激巨噬细胞凋亡。与细胞死亡相关的是真核起始因子 2 α (eIF2 α) 磷酸化的增强，在表达不能磷酸化的 eIF2 α 突变体的细胞中，PGJ(2) 对 caspase-3 激活的刺激作用增强。这些发现表明，虽然 PGJ(2) 诱导的 UPR 激活与细胞因子信号传导的抑制有关，但延长 UPR 激活会导致细胞死亡，并且 eIF2 α 磷酸化可能以保护性方式发挥作用，从而减弱细胞死亡。
PGJ(2)-stimulated beta-cell apoptosis is associated with prolonged UPR activation. Am J Physiol Endocrinol Metab 292: E1052-E1061, 2007. First published December 5, 2006; doi:10.1152/ajpendo.00274.2006. - Peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands have been shown to possess anti-inflammatory properties that include the inhibition of transcription factor activation and the expression of inflammatory genes. Using pancreatic beta-cells, we have shown that PPAR gamma ligands such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)) attenuate interferon-gamma-induced signal transducer and activator of transcription 1 activation and interleukin (IL)-1 beta-induced nuclear factor-kappa B activation by a pathway that correlates with endoplasmic reticulum stress and the induction of the unfolded protein response (UPR). The UPR is a conserved cellular response activated by a number of cell stressors and is believed to alleviate the stress and promote cell survival. However, prolonged activation of the UPR results in cellular death by apoptosis. In this report, we have examined the effects of PGJ(2) on UPR activation and the consequences of this activation on cell survival. Consistent with induction of a cell death pathway, treatment of rat islets and RINm5F cells for 24 h with PGJ(2) results in caspase-3 activation and caspase-dependent beta-cell death. The actions of these ligands do not appear to be selective for beta-cells, because PGJ(2) stimulates macrophage apoptosis in a similar fashion. Associated with cell death is the enhanced phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha), and in cells expressing a mutant of eIF2 alpha that cannot be phosphorylated, the stimulatory actions of PGJ(2) on caspase-3 activation are augmented. These findings suggest that, whereas PGJ(2)-induced UPR activation is associated with an inhibition of cytokine signaling, prolonged UPR activation results in cell death, and that eIF2 alpha phosphorylation may function in a protective manner to attenuate cell death.