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

• Published in: The Journal of biological chemistry 2016-04, Vol.291 (16), p.8428-8439
• Main Authors: Hong, Kyunghee, Xu, Guanlan, Grayson, Truman B., Shalev, Anath
• Format: Article
• Language: English
• Subjects: Animals; beta cell (B-cell); Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell Cycle Proteins; Cell Line, Tumor; cytokine; Cytokines - genetics; Cytokines - metabolism; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Endoplasmic Reticulum Stress - genetics; Gene Expression Regulation; Gene Regulation; Humans; Insulin-Secreting Cells - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Mice; microRNA (miRNA); MicroRNAs - biosynthesis; MicroRNAs - genetics; pancreatic islet; Rats; Signal Transduction; Thioredoxins - biosynthesis; Thioredoxins - genetics; TXNIP; type 1 diabetes
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.698365

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.