The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death
The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death
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DOI：
10.2337/db07-0944
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发表时间：
2008-01-01
期刊：
影响因子：
7.7
通讯作者：
Corbett, John A.
中科院分区：
文献类型：
--
作者：
Chambers, Kari T.;Unverferth, Juhe A.;Corbett, John A.
未折叠蛋白反应（UPR）是一种保守的细胞反应，旨在减轻损伤并促进细胞在经历应激时的存活；然而，长时间的UPR激活可导致凋亡细胞死亡。UPR被细胞因子诱导的一氧化氮（NO）产生激活，已被提出介导β细胞死亡以响应细胞因子。本研究探讨了UPR激活在细胞因子诱导的p细胞死亡中的作用。研究设计和方法：采用分子和生化方法研究细胞因子处理大鼠和人胰岛和RINm5F细胞对UPR激活、NO生成和细胞活力的影响。结果：upr激活与白细胞介素(IL)-1处理的大鼠胰岛β细胞死亡相关。NO介导细胞因子诱导的UPR激活和β细胞死亡，因为NO合成酶抑制剂减弱了这些il -1刺激的事件。重要的是，细胞因子和tunicamycin（一种经典的UPR激活剂）通过不同的机制诱导β细胞死亡。响应经典UPR激活剂的细胞死亡与caspase-3活性增加2.5倍相关，而IL-1不能刺激caspase-3活性。此外，在表达不能磷酸化的S51A eIF2 α突变体的tunicamycin处理的细胞或缺乏PERK（由RNA/内质网状样激酶调节的蛋白激酶）的细胞中，细胞死亡增加了35%。相反，PERK的缺失和S51A eIF2 α突变体的表达都不会影响细胞因子诱导的死亡水平。结论：虽然细胞因子诱导的β细胞死亡与UPR激活在时间上相关，但caspase活性缺乏和NO减弱caspase活性的能力表明，延长的UPR激活并不介导细胞因子诱导的β细胞死亡。
OBJECTEVE-The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress; however, prolonged UPR activation can result in apoptotic cell death. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate beta-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced P-cell death was examined.RESEARCH DESIGN AND METHODS-The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies.RESULTS-UPR activation correlates with beta-cell death in interleukin (IL)-1-treated rat islets. NO mediates both cytokine-induced UPR activation and beta-cell death as NO synthase inhibitors attenuate each of these IL-1-stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce beta-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity. In addition, cell death is enhanced by similar to 35% in tunicamycin-treated cells expressing an S51A eIF2 alpha mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulum-like kinase). In contrast, neither the absence of PERK nor the expression of the S51A eIF2 alpha mutant affects the levels of cytokine-induced death.CONCLUSIONS-While cytokine-induced beta-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced beta-cell death.