Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines

Oleson, Bryndon J.; McGraw, Jennifer; Broniowska, Katarzyna A.; Annamalai, Mani; Chen, Jing; Bushkofsky, Justin R; Davis, Dawn Belt; Corbett, John A.; Mathews, Clayton E.

doi:10.1152/ajpregu.00544.2014

Cited by 42 publications

(33 citation statements)

References 62 publications

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“…The weak cytokine-mediated activation of NFκB in EndoC-βH1 beta cells, as in human islets, failed to induce the iNOS pathway [22,24,33], which is at variance to rodent beta cells [7,13,19,21,[34][35][36][37][38][39]. Our results confirm recent studies in EndoC-βH1 beta cells that reported virtually no expression of iNOS [4,40]. In addition, we documented a lack of expression of other NOS isoforms: endothelial NOS and neuronal NOS.…”

Section: Discussionsupporting

confidence: 87%

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

et al. 2016

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Aims/hypothesis The aim of this study was to perform a detailed analysis of cytokine toxicity in the new human EndoC-βH1 beta cell line. Methods The expression profile of the antioxidative enzymes in the new human EndoC-βH1 beta cells was characterised and compared with that of primary beta cells in the human pancreas. The effects of proinflammatory cytokines on reactive oxygen species formation, insulin secretory responsiveness and apoptosis of EndoC-βH1 beta cells were determined. Results EndoC-βH1 beta cells were sensitive to the toxic action of proinflammatory cytokines. Glucose-dependent stimulation of insulin secretion and an increase in the ATP/ADP ratio was abolished by proinflammatory cytokines without induction of IL-1β expression. Cytokine-mediated caspase-3 activation was accompanied by reactive oxygen species formation and developed more slowly than in rodent beta cells. Cytokines transiently increased the expression of unfolded protein response genes, without inducing endoplasmic reticulum stress-marker genes. Cytokine-mediated NFκB activation was too weak to induce inducible nitric oxide synthase expression. The resultant lack of nitric oxide generation in EndoC-βH1 cells, in contrast to rodent beta cells, makes these cells dependent on exogenously generated nitric oxide, which is released from infiltrating immune cells in human type 1 diabetes, for full expression of proinflammatory cytokine toxicity. Conclusions/interpretation EndoC-βH1 beta cells are characterised by an imbalance between H 2 O 2 -generating and -inactivating enzymes, and react to cytokine exposure in a similar manner to primary human beta cells. They are a suitable beta cell surrogate for cytokine-toxicity studies.

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Section: Discussionsupporting

confidence: 87%

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

et al. 2016

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“…Release of hsp90a by vascular smooth muscle cells can be prompted by oxidative stress, 8 and reactive oxygen species such as nitric oxide (NO) are detected in human islets exposed to cytokines. 24 Furthermore, cytokine-induced apoptosis of primary rat beta cells and the rat beta cell line INS-1E is dependent on NO production. 25 Cytokine exposure increased transcript expression for the NO-generating enzyme iNOS in human bLox5 cells and cadaveric islets ( Fig.…”

Section: Beta Cell Hsp90a Release In Response To Cellular Inos Activitymentioning

confidence: 99%

Inflammatory stress of pancreatic beta cells drives release of extracellular heat‐shock protein 90α

et al. 2017

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A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at-risk individuals is the lack of well-established early biomarkers indicative of ongoing beta cell stress during the pre-clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat-shock protein 90 (hsp90) were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized that hsp90α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90α in response to stress induced by treatment with a combination of pro-inflammatory cytokines including interleukin-1β, tumour necrosis factor-α and interferon-γ. Mechanistically, hsp90α release was found to be driven by cytokine-induced endoplasmic reticulum stress mediated by c-Jun N-terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine-induced beta cell hsp90α release and JNK activation were significantly reduced by pre-treating cells with the endoplasmic reticulum stress-mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90α release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine-induced cell damage linked to autoimmunity.

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“…The EndoC-βH1 and -βH2 cells were generated from human fetal pancreatic bud and express numerous β-cell markers. These human β-cell lines respond to elevated glucose with stimulation of insulin secretion (7,8) and are increasingly used to explore various aspects of human β-cell biology (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Here, we monitored different parameters that constitute the triggering pathway of the GSIS (1,21), the electrophysiological and ultrastructural properties of EndoC-βH1 and -βH2 cells.…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological properties of human β-cell lines EndoC-βH1 and -βH2 conform with human β-cells

Hastoy

Godazgar

Clark

et al. 2017

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The electrophysiological and secretory properties of the human β-cell lines and EndoC-βH2 were investigated. Both cell lines respond to glucose (6-20mM) with 2-to 3-fold stimulation of insulin secretion, an effect that was mimicked by tolbutamide (0.2mM) and reversed by diazoxide (0.5mM). Glucose-induced insulin release correlated with an elevation of [Ca 2+ ]i, membrane depolarization and increased action potential firing. KATP channel activity at 1mM glucose is low and increasing glucose to 6 or 20mM reduced KATP channel activity to the same extent as application of the KATP channel blocker tolbutamide (0.2mM). The upstroke of the action potentials in EndoC-βH1 and -βH2 cells observed at high glucose principally reflects activation of L-and P/Q-type Ca 2+ channels with some small contribution of TTX-sensitive Na + channels.Action potential repolarization involves activation of voltage-gated Kv2.2 channels and large-conductance Ca 2+ -activated K + channels. Exocytosis (measured by measurements of membrane capacitance) was triggered by membrane depolarizations >10ms to membrane potentials above -30mV. Both cell lines were well-granulated (6,000-15,000 granules/cell) and granules consisted of a central insulin core surrounded by a clear halo. We conclude that the EndoC-βH1 and -βH2 cells share many features of primary human β-cells and that they represent a useful experimental model.

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Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines

Cited by 42 publications

References 62 publications

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines

Inflammatory stress of pancreatic beta cells drives release of extracellular heat‐shock protein 90α

Electrophysiological properties of human β-cell lines EndoC-βH1 and -βH2 conform with human β-cells

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