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01.10.2015 | Article

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

verfasst von: Flora Brozzi, Tarlliza R. Nardelli, Miguel Lopes, Isabelle Millard, Jenny Barthson, Mariana Igoillo-Esteve, Fabio A. Grieco, Olatz Villate, Joana M. Oliveira, Marina Casimir, Marco Bugliani, Feyza Engin, Gökhan S. Hotamisligil, Piero Marchetti, Decio L. Eizirik

Erschienen in: Diabetologia | Ausgabe 10/2015

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Abstract

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, cytokine-induced ER stress involves NO production and consequent inhibition of the ER Ca²⁺ transporting ATPase sarco/endoplasmic reticulum Ca²⁺ 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 cytokine-induced 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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Titel: Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms
verfasst von: Flora Brozzi
Tarlliza R. Nardelli
Miguel Lopes
Isabelle Millard
Jenny Barthson
Mariana Igoillo-Esteve
Fabio A. Grieco
Olatz Villate
Joana M. Oliveira
Marina Casimir
Marco Bugliani
Feyza Engin
Gökhan S. Hotamisligil
Piero Marchetti
Decio L. Eizirik
Publikationsdatum: 01.10.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 10/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3669-6

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Abstract

Aims/hypothesis

Methods

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