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

Abstract

Thioredoxin-interacting protein (TXNIP) is a key regulator of diabetic ␤-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 ␣ (TNF␣), interleukin-1␤ (IL-1␤), and interferon ␥ (IFN␥) 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 ␤-cell TXNIP expression; however, although TNF␣ had no effect, IL-1␤ surprisingly down-regulated TXNIP transcription, whereas IFN␥ increased TXNIP levels in INS-1 ␤-cells and primary islets. Human TXNIP promoter analyses and chromatin immunoprecipitation studies revealed that the IL-1␤ effect was mediated by inhibition of carbohydrate response element binding protein activity. In contrast, IFN␥ increased pro-apoptotic TXNIP post-transcriptionally via induction of endoplasmic reticulum stress, activation of inositol-requiring enzyme 1␣ (IRE1␣), and suppression of miR-17, a microRNA that targets and down-regulates TXNIP. In fact, miR-17 knockdown was able to mimic the IFN␥ effects on TXNIP, whereas miR-17 overexpression blunted the cytokine effect. Thus, our results demonstrate for the first time that the proinflammatory cytokines TNF␣, IL-1␤, and IFN␥ each have distinct and in part opposing effects on ␤-cell TXNIP expression. These findings thereby provide new mechanistic insight into the regulation of TXNIP and ␤-cell biology and reveal novel links between proinflammatory cytokines, carbohydrate response element binding protein-mediated transcription, and microRNA signaling.Pancreatic ␤-cell dysfunction and death play a central role in the development and progression of diabetes and can be caused by multiple stressors including glucotoxicity, gluco-lipotoxicity, and cytokine toxicity (1, 2). Glucotoxicity induced by chronic exposure of ␤-cells to high levels of glucose promotes ␤-cell apoptosis, resulting in a vicious cycle with further worsening of the hyperglycemia (1). Interestingly, we previously discovered thioredoxin-interacting protein (TXNIP), 2 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). Moreover, we recently revealed that elevated TXNIP levels also contribute to ␤-cell dysfunction by inducing microRNA expression (miR-204), which in turn targets the insulin transcription factor MafA and thereby inhibits insulin production (7). In contrast, TXNIP deficiency led to an increase in functional ␤-cell mass and pro...

TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation

“…As a negative regulator of thioredoxin (TRX), TXNIP was found to be an inducer of the intracellular level of reactive oxygen species (ROS) (12). A number of studies have confirmed that TXNIP shows strong growth suppressive, metastasis inhibitory and proapoptotic functions (13,14).…”

Short Report: Circulating microRNAs are associated with incident diabetes over 10 years in Japanese Americans

“…Some identified miRNAs have functions in islet cells as well. In pancreatic cell lines, miR-17 downregulates thioredoxin-interacting protein, a pro-apoptotic regulator of beta-cells in diabetes 22 . In mouse islets, miR-7 (miR-7a) targets multiple components of the mTOR signaling pathway, and its inhibition promotes adult beta-cell replication 23 .…”

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…TXNIP was originally identified as a negative regulator of thioredoxin (Muoio, 2007), and subsequent studies found that TXNIP contributes to a wide array of processes in several tissues. Notably, TXNIP causes an increase in intracellular reactive oxygen species generation (Hong et al, 2016) that may inhibit hepatocellular carcinoma cell proliferation (Li et al, 2017a). TXNIP is key regulator of NLRP3 inflammasome activation, which plays an important role in liver fibrosis and hepatocellular carcinoma (Ringelhan et al, 2018;Wree et al, 2017), and its activation is associated with the NLRP3 inflammasome pathway in human diseases (Bai et al, 2019;Kim et al, 2019;Li et al, 2019).…”