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J Biol Chem. 2016 Apr 15;291(16):8428-39. doi: 10.1074/jbc.M115.698365. Epub 2016 Feb 8.

Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways.

Author information

1
From the Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
2
From the Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294 shalev@uab.edu.

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.

KEYWORDS:

TXNIP; beta cell (B-cell); cytokine; microRNA (miRNA); pancreatic islet; type 1 diabetes

PMID:
26858253
PMCID:
PMC4861417
DOI:
10.1074/jbc.M115.698365
[Indexed for MEDLINE]
Free PMC Article

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