Cytokines Downregulate the Sarcoendoplasmic Reticulum Pump Ca2+ ATPase 2b and Deplete Endoplasmic Reticulum Ca2+, Leading to Induction of Endoplasmic Reticulum Stress in Pancreatic β-Cells

Cardozo, Alessandra K; Ortis, Fernanda; Størling, Joachim; Feng, Yingmei; Rasschaert, Joanne; Tonnesen, Morten; Eylen, Françoise Van; Mandrup-Poulsen, Thomas; Herchuelz, André; Eizirik, Décio L.

doi:10.2337/diabetes.54.2.452

Cited by 490 publications

(526 citation statements)

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“…Thus while some studies suggest that C/EBP homologous protein (CHOP) [7] and binding immunoglobulin protein (BIP) [8] play proand anti-apoptotic roles in this process respectively, others failed to observe any association between ER-stress markers and cytokine-induced beta cell apoptosis [9][10][11]. We observed that the cytokine-induced ER-stress response is atypical and characterised by strong induction of the pro-apoptotic PERK-ATF4-CHOP branch of the UPR, but with defective XBP1 splicing and ATF6 activation [2,12]. We also showed that IFN-γ alone decreases expression of Xbp1s and several ER chaperones [12].…”

Section: Introductionmentioning

confidence: 66%

“…Dispersed islets or FACS-purified beta cells were pre-cultured in complete beta cell medium supplemented with 5% heat-inactivated FBS from 20 to 48 h for recovery [15]. Experiments were then conducted in medium without serum [2,13]. Rat fibroblast 208F cells (ECACC, Salisbury, UK) were cultured in DMEM supplemented with 10% FCS [16].…”

Section: Methodsmentioning

confidence: 99%

“…The sarco/endoplasmic reticulum calcium ATPase-2 inhibitor, cyclopiazonic acid (CPA) (Sigma-Aldrich, Bornem, Belgium), which induces rapid depletion of ER Ca 2+ thus leading to ER-stress was dissolved in DMSO and used at a concentration of 25 μmol/l in beta cells and 50 μmol/l in 208F [2,19] Generation of recombinant adenoviruses and cell infection To produce XBP1 in insulin-secreting cells, we generated recombinant adenoviruses comprising fragments of the mouse Xbp1 (mXbp1) mRNA (gi|18139942|gb| AF443192.1) [20]. The following primers (Electronic supplementary material [ESM] Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Proinflammatory cytokines released by immune cells invading the islets contribute to beta cell dysfunction and apoptosis during insulitis [1]. We have previously shown that cytokines deplete endoplasmic reticulum (ER) Ca 2+ stores, leading to activation of the unfolded protein response (UPR) [2]. The UPR seeks to restore normal ER function by attenuating translation, increasing folding capacity through upregulation of ER chaperones and promoting degradation of misfolded proteins via the ER-associated degradation (ERAD) pathway.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…Other proinflammatory cytokines can downregulate an ER Ca 2ϩ ATPase (SERCA2b), which in turn lowers the threshold for UPR activation in response to ER stress (26). It is also possible that IFNs could enhance the tendency of HLA-B27 to misfold.…”

Section: Discussionmentioning

confidence: 99%

HLA–B27 up‐regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis‐like disease

Turner¹,

DeLay²,

Bai³

et al. 2007

Arthritis & Rheumatism

126

103

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Objective. HLA-B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA-B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA-B27/human ␤ 2 -microglobulin-transgenic (B27-transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA-B27-induced UPR and to determine whether splenocytes respond in a similar manner.Methods. Splenocytes were isolated and bone marrow macrophages were derived from B27-transgenic and wild-type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA-B27 expression and misfolding were assessed by real-time reverse transcription-polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X-box binding protein 1 messenger RNA (mRNA) splicing.Results. HLA-B27 mRNA up-regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA-B27 up-regulation. In contrast, B27-transgenic splenocytes exhibited only low-level differences in the expression of UPR target genes after exposure to interferon-␥ or concanavalin A, which resulted in minimal HLA-B27 up-regulation.Conclusion. These results suggest that HLA-B27-associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA-B27 misfolding. Strategies that eliminate HLA-B27 up-regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA.HLA-B27, a class I major histocompatibility complex (MHC) allele, is a major predisposing factor for the development of ankylosing spondylitis and other spondylarthritides (SpA) (1). In many populations, Ͼ90% of patients with ankylosing spondylitis are HLA-B27 positive, compared with Ͻ10% of healthy controls, highlighting this as one of the strongest HLA disease associations. However, despite 3 decades of investigation, the molecular contribution of HLA-B27 to the pathogenesis of SpA remains incompletely defined.It was previously reported that HLA-B27/human ␤ 2 -microglobulin (Hu␤ 2 m)-transgenic (B27-transgenic) rats develop an SpA-like inflammatory disease with a phenotype that includes arthritis and colitis, whereas HLA-B7/Hu␤ 2 m-transgenic (B7-transgenic) rats re-

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To eat or not to eat – Anti‐ageing effects of energy restriction

Neves

Martins

Passos

et al. 2015

Anti‐ageing Nutrients

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Cytokines Downregulate the Sarcoendoplasmic Reticulum Pump Ca2+ ATPase 2b and Deplete Endoplasmic Reticulum Ca2+, Leading to Induction of Endoplasmic Reticulum Stress in Pancreatic β-Cells

Cited by 490 publications

References 51 publications

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

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

HLA–B27 up‐regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis‐like disease

To eat or not to eat – Anti‐ageing effects of energy restriction

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