Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways
Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways
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DOI：
10.1074/jbc.m115.698365
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发表时间：
2016-04-15
影响因子：
4.8
通讯作者：
Shalev, Anath
中科院分区：
文献类型：
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作者：
Hong, Kyunghee;Xu, Guanlan;Shalev, Anath
硫氧还蛋白相互作用蛋白（TXNIP）是糖尿病β细胞凋亡和功能障碍的关键调节因子，在1型和2型糖尿病小鼠模型中，抑制TXNIP可预防糖尿病。尽管我们之前已表明葡萄糖可强烈诱导TXNIP，但促炎细胞因子肿瘤坏死因子α（TNFα）、白细胞介素 - 1β（IL - 1β）和干扰素γ（IFNγ）对其的调节作用在很大程度上仍未被探索。此外，尽管这种三种细胞因子混合物被广泛用于在体外模拟1型糖尿病，但其涉及的机制尚未完全清楚。有趣的是，我们现在发现这种细胞因子混合物会增加β细胞中TXNIP的表达；然而，尽管TNFα没有作用，令人惊讶的是IL - 1β会下调TXNIP转录，而IFNγ会增加INS - 1β细胞和原代胰岛中TXNIP的水平。对人TXNIP启动子的分析和染色质免疫沉淀研究表明，IL - 1β的作用是通过抑制碳水化合物反应元件结合蛋白活性来介导的。相比之下，IFNγ通过诱导内质网应激、激活肌醇需求酶1α（IRE1α）以及抑制靶向并下调TXNIP的微小RNA miR - 17，在转录后增加促凋亡的TXNIP。事实上，miR - 17的敲低能够模拟IFNγ对TXNIP的作用，而miR - 17的过表达则减弱了细胞因子的作用。因此，我们的结果首次表明促炎细胞因子TNFα、IL - 1β和IFNγ对β细胞TXNIP表达各自具有独特且部分相反的作用。这些发现从而为TXNIP的调节和β细胞生物学提供了新的机制见解，并揭示了促炎细胞因子、碳水化合物反应元件结合蛋白介导的转录和微小RNA信号传导之间的新联系。
Thioredoxin-interacting protein (TXNIP) is a key regulator of diabetic beta-cell apoptosis and dysfunction, and TXNIP inhibition prevents diabetes in mouse models of type 1 and type 2 diabetes. Although we have previously shown that TXNIP is strongly induced by glucose, any regulation by the proinflammatory cytokines tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and interferon gamma (IFN gamma) has remained largely unexplored. Moreover, even though this three-cytokine mixture is widely used to mimic type 1 diabetes in vitro, the mechanisms involved are not fully understood. Interestingly, we have now found that this cytokine mixture increases beta-cell TXNIP expression; however, although TNF alpha had no effect, IL-1 beta surprisingly down-regulated TXNIP transcription, whereas IFN gamma increased TXNIP levels in INS-1 beta-cells and primary islets. Human TXNIP promoter analyses and chromatin immunoprecipitation studies revealed that the IL-1 beta effect was mediated by inhibition of carbohydrate response element binding protein activity. In contrast, IFN gamma increased pro-apoptotic TXNIP post-transcriptionally via induction of endoplasmic reticulum stress, activation of inositol-requiring enzyme 1 alpha (IRE1 alpha), and suppression of miR-17, a microRNA that targets and down-regulates TXNIP. In fact, miR-17 knockdown was able to mimic the IFN gamma effects on TXNIP, whereas miR-17 overexpression blunted the cytokine effect. Thus, our results demonstrate for the first time that the proinflammatory cytokines TNF alpha, IL-1 beta, and IFN gamma each have distinct and in part opposing effects on beta-cell TXNIP expression. These findings thereby provide new mechanistic insight into the regulation of TXNIP and beta-cell biology and reveal novel links between proinflammatory cytokines, carbohydrate response element binding protein-mediated transcription, and microRNA signaling.