Transcriptional and translational regulation of cytokine signaling in inflammatory β-cell dysfunction and apoptosis

Novotny, Guy Wayne; Lundh, Morten; Backe, Marie Balslev; Christensen, Dan Ploug; Hansen, Jakob Bondo; Dahllöf, Mattias Salling; Pallesen, Emil M.H.; Mandrup-Poulsen, Thomas

doi:10.1016/j.abb.2012.09.014

Cited by 32 publications

(21 citation statements)

References 237 publications

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“…Development of type 1 diabetes mellitus is associated with a progressive cellular dysfunction and damage, leading ultimately to b-cell death (Eizirik & Mandrup-Poulsen 2001, Novotny et al 2012. As shown in previous studies, many steps in this process are mediated by ROS including also interactions with nitric oxide (Gurgul-Convey et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Lortz

Schröter

Stückemann

et al. 2014

Journal of Molecular Endocrinology

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Free intracellular ferrous iron (Fe 2C ) is essential for the generation of the extremely toxic hydroxyl radicals, which contribute to b-cell destruction by cytokines. Therefore the expression of the different divalent metal transporter 1 (Dmt1) isoforms and ferritin (Ft) subunits, responsible for iron import and chelation, was analyzed under pro-inflammatory conditions (IL1b alone or together with TNFaCIFNg). The Dmt1 isoforms (1A/1B and CIRE/ KIRE) and the total Dmt1 expression in insulin-producing cells (RINm5F and INS-1E), in primary rat islets and, for comparison, in the neuroendocrine PC12 cell line were quantified by qRT-PCR. In addition, the expression of the light (L-Ft) and heavy Ft (H-Ft) subunits and the mitochondrial Ft isoform (Mtft) in insulin-producing cells under control conditions and after cytokine treatment was estimated. The 1B isoform was the predominant Dmt1 mRNA in all insulin-producing cells, accounting for almost 100% of the 1A/1B isoform expression. For the IRE variants, CIRE expression was higher than KIRE expression. Pro-inflammatory cytokines accelerated the expression of Dmt1 isoforms significantly with an overall 2.5-to 3-fold increase in the total Dmt1 expression. In contrast, the expression of the iron-buffering ferritin subunits L-and H-Ft was unaffected by IL1b and only slightly induced by the cytokine mixture. Mtft expression was also not increased. Dmt1 expression was significantly elevated through pro-inflammatory cytokines, whereas Ft expression was marginally increased. This imbalance between the increased iron transport capacity and the almost unaffected iron storage capacity can foster cytokine-mediated formation of hydroxyl radicals and thus pro-inflammatory cytokine toxicity through elevated free iron concentrations.

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Section: Discussionmentioning

confidence: 99%

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Lortz

Schröter

Stückemann

et al. 2014

Journal of Molecular Endocrinology

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“…Chronic exposure to elevated IL-1 causes beta cell death and dysfunction due to altered gene transcription, changes in protein activity, and induction of oxidative stress (25). Data from clinical studies suggest that anti-IL-1 agents can improve beta cell function without affecting insulin sensitivity (17).…”

Section: Discussionmentioning

confidence: 99%

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Westwell‐Roper¹,

Denroche

Ehses

et al. 2016

Journal of Biological Chemistry

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Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1␤ secretion by stimulating both the synthesis and processing of proIL-1␤, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1␤ synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2-(TLR2-) dependent stimulus for NF-B activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Nonamyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1␤ secretion, whereas late IAPP aggregates induced NLRP3-dependent IL-1␤ secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPPinduced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction.

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“…Data represent means ± SEM of four to six mice per group. *p<0.05, **p<0.01, ***p<0.001 Discussion Chronic exposure to elevated IL-1 causes beta cell death and dysfunction due to altered gene transcription, changes in protein activity and induction of oxidative stress [22]. Data from clinical studies suggest that anti-IL-1 agents can improve beta cell function without affecting insulin sensitivity [12].…”

Section: Il-1ra Limits Islet Amyloid Formation In Lean A-hiappmentioning

confidence: 99%

IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice

et al. 2014

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Aims/hypothesis Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to beta cell dysfunction in type 2 diabetes. Human but not non-amyloidogenic rodent IAPP induces islet macrophage proIL-1β synthesis. We evaluated the effect of IL-1 receptor antagonist (IL-1Ra) on islet inflammation and dysfunction in a mouse model of type 2 diabetes with amyloid formation. Methods Lean and obese male mice (A/a or A vy /A at the agouti locus, respectively) with or without beta cell human IAPP expression (hIAPP Tg/0 ) were treated with PBS or IL-1Ra (50 mg kg) from 16 weeks of age. Intraperitoneal glucose and insulin tolerance tests were performed after 8 weeks. Pancreases were harvested for histology and gene expression analysis. Results Aggregation of human IAPP was associated with marked upregulation of proinflammatory gene expression in islets of obese hIAPP Tg/0 mice, together with amyloid deposition and fasting hyperglycaemia. IL-1Ra improved glucose tolerance and reduced plasma proinsulin:insulin in both lean and obese hIAPP Tg/0 mice with no effect on insulin sensitivity. The severity and prevalence of islet amyloid was reduced by IL-1Ra in lean hIAPP Tg/0 mice, suggesting a feed-forward mechanism by which islet inflammation promotes islet amyloid at the early stages of disease. IL-1Ra limited Il1a, Il1b, Tnf and Ccl2 expression in islets from obese hIAPP Tg/0 mice, suggesting an altered islet inflammatory milieu. Conclusions/interpretation These data provide the first in vivo evidence-using a transgenic mouse model with amyloid deposits resembling those found in human islets-that IAPP-induced beta cell dysfunction in type 2 diabetes may be mediated by IL-1. Anti-IL-1 therapies may limit islet inflammation and dysfunction associated with amyloid formation.

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Transcriptional and translational regulation of cytokine signaling in inflammatory β-cell dysfunction and apoptosis

Cited by 32 publications

References 237 publications

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice

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