Abstract
Thioredoxin-interacting protein (TXNIP) is a key regulator of diabetic β-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 α (TNFα), interleukin-1β (IL-1β), and interferon γ (IFNγ) 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 β-cell TXNIP expression; however, although TNFα had no effect, IL-1β surprisingly down-regulated TXNIP transcription, whereas IFNγ increased TXNIP levels in INS-1 β-cells and primary islets. Human TXNIP promoter analyses and chromatin immunoprecipitation studies revealed that the IL-1β effect was mediated by inhibition of carbohydrate response element binding protein activity. In contrast, IFNγ increased pro-apoptotic TXNIP post-transcriptionally via induction of endoplasmic reticulum stress, activation of inositol-requiring enzyme 1α (IRE1α), and suppression of miR-17, a microRNA that targets and down-regulates TXNIP. In fact, miR-17 knockdown was able to mimic the IFNγ effects on TXNIP, whereas miR-17 overexpression blunted the cytokine effect. Thus, our results demonstrate for the first time that the proinflammatory cytokines TNFα, IL-1β, and IFNγ each have distinct and in part opposing effects on β-cell TXNIP expression. These findings thereby provide new mechanistic insight into the regulation of TXNIP and β-cell biology and reveal novel links between proinflammatory cytokines, carbohydrate response element binding protein-mediated transcription, and microRNA signaling.
Highlights
Ening of the hyperglycemia [1]
We previously discovered that thioredoxin-interacting protein (TXNIP) is a key mediator of -cell apoptosis induced by glucotoxicity [5], whereas TXNIP expression is not induced by free fatty acids or in the context of lipotoxicity [6]
We further found that IL-1 treatment resulted in a ϳ70% decrease in TXNIP mRNA levels (Fig. 1C), whereas IFN␥ significantly increased TXNIP mRNA levels Ͼ2-fold (Fig. 1D), which is consistent with the mild net increase observed in response to the cytokine combination
Summary
Ening of the hyperglycemia [1]. Interestingly, we previously discovered thioredoxin-interacting protein (TXNIP), a ubiquitously expressed cellular redox regulator [3], as the top glucoseinduced gene in a human islet gene expression microarray study [4] and found that TXNIP is a crucial mediator of glucotoxicity-induced -cell apoptosis [5]. We further demonstrated that -cell TXNIP expression is up-regulated in diabetes and that TXNIP-induced -cell death is mediated by the intrinsic/ mitochondrial death pathway [6]. Unlike glucose, elevated free fatty acids do not increase -cell TXNIP expression, and TXNIP deficiency does not effectively protect against fatty acid-induced -cell death [6, 10]. This suggests that different -cell stressors have distinct effects on TXNIP expression and raises the question of how cytokines might affect -cell TXNIP. TXNIP is induced by diabetes and various stressors and, similar to cytokines, has been shown to promote -cell apoptosis and dysfunction, but the potential link between proinflammatory cytokines and pro-apoptotic TXNIP has remained largely unexplored. The aim of the present study was to investigate whether cytokines might regulate -cell TXNIP expression and to determine the molecular mechanisms involved
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