title: Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways.
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.
authors: From the Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors: Kyunghee
authors: K
authors: Hong
authors: From the Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors: Guanlan
authors: G
authors: Xu
authors: From the Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors: Truman B
authors: TB
authors: Grayson
authors: 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.
authors: Anath
authors: A
authors: Shalev
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D013879:Thioredoxins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; C508585:IL1B protein, human; D053583:Interleukin-1beta; C524941:MIRN17 microRNA, human; C000601368:MIRN17 microRNA, rat; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C486715:TXNIP protein, human; C493796:TXNIP protein, rat; C445672:Txnip protein, mouse; D013879:Thioredoxins
keywords: TXNIP; beta cell (B-cell); cytokine; microRNA (miRNA); pancreatic islet; type 1 diabetes