Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells

Ortis, Fernanda; Pirot, Pierre; Naamane, Najib; Kreins, Alexandra; Rasschaert, Joanne; Moore, Fabrice; Théâtre, Emilie; Verhaeghe, Catherine; Magnusson, Nils E.; Chariot, Alain; Ørntoft, Torben F.; Eizirik, Décio L.

doi:10.1007/s00125-008-0999-7

Cited by 141 publications

(154 citation statements)

References 49 publications

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“…The significant protection against cytokinedependent human beta cell apoptosis with TUDCA and the small, although significant, protection after blocking the ER-stress-induced pro-apoptotic transcription factor CHOP support the contribution of ER stress in this process. In a final series of experiments we identified JNK activation as a downstream mechanism leading to human beta cell apoptosis, which is in line with previous observations in rodent beta cells [50,51]. Interestingly, TUDCA significantly decreased cytokine-induced JNK activation, providing a mechanistic explanation for the protective effect of this chemical chaperone against cytokine-induced human beta cell apoptosis.…”

Section: Discussionsupporting

confidence: 88%

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

et al. 2015

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Aims/hypothesis Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokineinduced ER stress involves NO production and consequent inhibition of the ER Ca 2+ transporting ATPase sarco/ endoplasmic reticulum Ca 2+ pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field. Methods Rat and mouse insulin-producing cells, human pancreatic islets and human EndoC-βH1 cells were exposed to the cytokines IL-1β, TNF-α and IFN-γ, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokineinduced apoptosis of human beta cells. Results NO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis. Conclusions/interpretation These observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation.

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Section: Discussionsupporting

confidence: 88%

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

et al. 2015

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“…Knocking down CHOP also partly blocked the induction of the chemokines (C-X-C motif) ligand 10 (CXCL10; Figure 6d) and the cytokine IL15 (Figure 6e) in primary b-cells in response to TNF-a þ IFN-g, but had no effect on the minor induction obtained in response to IL-1b þ IFN-g. These chemokines are co-regulated by IFN regulatory factor 7 (IRF7), 33 which is mostly a TNF-a-dependent gene. In line with this, knocking down CHOP decreased TNF-a þ IFN-ginduced IRF-7 mRNA overexpression (Figure 6f).…”

Section: Resultsmentioning

confidence: 99%

“…After transfection (16 h), cells were exposed to cytokines for 8 h. Sample preparation, luciferase activities and values correction were performed as described previously. 33 Transient overexpression of rat CHOP was achieved using the fulllength cDNA clone, cloned in the expression vector p-CMV-SPORT6 purchased from Open Biosystems (clone 7932840; Thermo Fisher Scientific, Perbio Science).…”

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confidence: 99%

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

et al. 2012

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Induction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic b-cells. Pro-inflammatory cytokines are early mediators of b-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in b-cells, but the role for CHOP overexpression in cytokine-induced b-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-jB (NF-jB) is a crucial transcription factor regulating b-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-jB activity and expression of key NF-jB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IjB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting b-cell death: (1) CHOP directly contributes to cytokine-induced b-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-jB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis. Type 1 diabetes (T1D) is a severe chronic disease resulting from an autoimmune destruction of the pancreatic b-cells. The incidence of T1D has been rising steadily in developed countries from the 1950s to the present day, with the recent, alarming prediction that it will double in children under the age of 5 years by 2020. 1 b-cell loss in T1DM occurs slowly over years and 480% of the b-cell mass is usually lost at the time of diagnosis. Because of the excessive mortality associated with complications of T1D and the increasing incidence of childhood diabetes, 2 there is an ongoing effort to develop novel strategies for a better treatment and hopefully, prevention of T1D.In T1D, b-cells cooperate with the immune system to its own destruction by activating pro-apoptotic pathways and secreting chemokines/cytokines that contribute to islet inflammation. 3 These responses are mostly triggered via the secretion of the pro-inflammatory cytokines interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g) by the infiltrated immune cells. The mechanisms regulating cytokine-mediated b-cell apoptosis and pro-inflammatory responses are intricate and include, but are not restricted to, the activation of the transcription factors nuclear factor-kB (NF-kB) and STAT-1, the c-Jun N-terminal kinases (JNK), endoplasmic reticulum (ER) stress pathways and the intrinsic mitochondrial apoptotic pathways. [3][4][5][6][7] NF-kB activation is due to cytokine-dependent activation of the inhibitor of k-light polypeptide gene enha...

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“…The cells were examined by inverted fluorescence microscopy (Axiovert 200; Carl Zeiss, Zaventem, Belgium). A kit for live cells (NunView 488 Caspase-3 Kit; Biotium, Hayward, CA, USA) was used to determine caspase-3 activation [26]. A minimum of 500 cells were counted in each experimental condition and viability or caspase activity was evaluated by two independent observers, one of them unaware of sample identity.…”

Section: Methodsmentioning

confidence: 99%

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

et al. 2010

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Aims/hypothesis Pro-inflammatory cytokines involved in the pathogenesis of type 1 diabetes deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to ER-stress and beta cell apoptosis. However, the cytokine-induced ER-stress response in beta cells is atypical and characterised by induction of the pro-apoptotic PKR-like ER kinase (PERK)-C/EBP homologous protein (CHOP) branch of the unfolded protein response, but defective X-box binding protein 1 (XBP1) splicing and activating transcription factor 6 activation. The purpose of this study was to overexpress spliced/active Xbp1 (XBP1s) to increase beta cell resistance to cytokine-induced ER-stress and apoptosis.Methods Xbp1s was overexpressed using adenoviruses and knocked down using small interference RNA in rat islet cells. In selected experiments, Xbp1 was also knocked down in FACS-purified rat beta cells and rat fibroblasts. Expression and production of XBP1s and key downstream genes and proteins was measured and beta cell function and viability were evaluated.

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Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic beta cells

Cited by 141 publications

References 49 publications

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

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