Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes

Marhfour, Ihsane; Lopez, Xavier Moles; Lefkaditis, Dionysios; Salmon, Isabelle; Allagnat, Florent; Richardson, Sarah J.; Morgan, Noel G.; Eizirik, Décio L.

doi:10.1007/s00125-012-2604-3

Cited by 214 publications

(177 citation statements)

References 11 publications

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“…Furthermore, histological analysis and other approaches have identified higher expression of type I IFNs in islets from patients with type 1 diabetes [7][8][9][10], and self-reactive antibodies targeting type I IFNs are associated with protection against type 1 diabetes in patients with an autoimmune syndrome [20]. Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I [1,2], ER stress [3,37] and beta cell apoptosis [6], and we presently show that IFNα induces or contributes to these three phenomena in human beta cells.…”

Section: Discussionmentioning

confidence: 99%

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Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.Results IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

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Section: Discussionmentioning

confidence: 99%

“…Three hallmarks of the pancreatic islets in early human type 1 diabetes and in mouse models of the disease are overexpression of HLA class I [1,2], presence of markers of endoplasmic reticulum (ER) stress [3][4][5] and beta cell apoptosis [6]. The mediator(s) of these phenomena, however, remain(s) to be defined.…”

Section: Introductionmentioning

confidence: 99%

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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“…Alexa Fluor fluorescent secondary antibodies (Molecular Probes-Invitrogen, Leiden, the Netherlands) were applied for 1 h at room temperature (ESM Table 2). Immunofluorescence was visualised on a Zeiss microscope equipped with a camera (Zeiss-Vision, Munich, Germany), as previously described [38].…”

Section: Assessment Of Cell Viabilitymentioning

confidence: 99%

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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Aims/hypothesis Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Methods Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ.RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. Results IL-17A augmented IL-1β+IFN-γ-and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine-or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice. Conclusions/interpretation Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis.

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“…Markers of the UPR are expressed in inflamed islets in vivo, in both samples from NOD mice [8,9] and pancreatic sections of individuals with type 1 diabetes [10]. ER stress is also induced when pancreatic islets or purified beta cells are exposed in vitro to cytokines [2,11].…”

Section: Introductionmentioning

confidence: 99%

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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Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes

Cited by 214 publications

References 11 publications

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

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

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