Short Term Exposure of Beta Cells to Low Concentrations of Interleukin-1β Improves Insulin Secretion through Focal Adhesion and Actin Remodeling and Regulation of Gene Expression

Arous, Caroline; Ferreira, Pedro G.; Dermitzakis, Emmanouil T.; Halban, Philippe A.

doi:10.1074/jbc.m114.611111

Cited by 31 publications

(37 citation statements)

References 68 publications

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“…Consistent with previous reports (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), acute exposure to IL-1β (10 ng/ml) enhanced glucose-stimulated insulin secretion from mouse ( Figure 1A) and human ( Figure 1B) islets. IL-1β had no effect on islet insulin content and did not affect secretion at low glucose (data not shown).…”

Section: Resultssupporting

confidence: 81%

“…One of several proposed mechanisms underlying the IL-1β-mediated potentiation of insulin secretion is an IL-1β-induced rise in [Ca 2+ ] i (32,38,39). While it is known that the insulinotropic effect of IL-1β requires Ca 2+ flux into the β cell (31,34), whether the stimulatory effects of IL-1β are due to an increase in [Ca 2+ ] i is still debated (29,30,32,34,38). To provide further insight into the mechanism of IL-1β-stimulated insulin release, Ca 2+ currents and [Ca 2+ ] i were measured following treatment with IL-1β.…”

Section: Resultsmentioning

confidence: 99%

“…In support of this, IL-1β acts directly on β cells to potentiate glucose-stimulated insulin secretion from perfused pancreata (23,24), isolated islets (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), and purified β cells (38). Although several potential mechanisms of IL-1β-potentiated insulin secretion have been proposed (37)(38)(39), the role of both intracellular Ca 2+ ([Ca 2+ ] i ) and the amplification pathway in this process remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1 signaling contributes to acute islet compensation

Hajmrle¹,

Smith²,

Spigelman³

et al. 2016

JCI Insight

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin-1 signaling contributes to acute islet compensation

Hajmrle¹,

Smith²,

Spigelman³

et al. 2016

JCI Insight

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“…Although IL-1␤ has been implicated in ␤-cell destruction (42,43), it has been suggested that IL-1␤ itself is not sufficient to cause ␤-cell death and that low concentration or short term treatment with IL-1␤ may even have beneficial effects on ␤-cell function and survival (44,45), which is in alignment with the observed reduction in pro-apoptotic TXNIP expression. Interestingly, TXNIP has previously been shown to be involved in inflammasome activation and to thereby induce IL-1␤ production (46).…”

Section: Discussionsupporting

confidence: 57%

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

Hong

Grayson

et al. 2016

Journal of Biological Chemistry

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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...

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“…Whatever the source, the effects of cytokines on beta cell function and survival depend on several other factors, including, in particular, their concentrations and combinations. For example, low levels of IL-1β promote beta cell proliferation and improve insulin secretion [41,42]; furthermore, when human beta cell preparations were cultured for 48 or 72 h with or without IL-1β, TNFα or IFNγ, none of these single cytokines was toxic to the beta cells [43].…”

Section: Islet Expression Of Cytokines and Chemokines In Type 2 Diabetesmentioning

confidence: 99%