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

• Published in: Diabetologia Vol. 58; no. 10; pp. 2307 - 2316
• Main Authors: Brozzi, Flora, Nardelli, Tarlliza R., Lopes, Miguel, Millard, Isabelle, Barthson, Jenny, Igoillo-Esteve, Mariana, Grieco, Fabio A., Villate, Olatz, Oliveira, Joana M., Casimir, Marina, Bugliani, Marco, Engin, Feyza, Hotamisligil, Gökhan S., Marchetti, Piero, Eizirik, Decio L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2015; Springer Nature B.V
• Subjects: Animals; Apoptosis; Cell death; Cell Line; Cell Survival - drug effects; Cytokines; Cytokines - pharmacology; Diabetes; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Enzyme Inhibitors - pharmacology; Gene expression; Human Physiology; Humans; Insulin; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Interferon-gamma - pharmacology; Interleukin-1beta - pharmacology; Internal Medicine; Kinases; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Nitric Oxide Synthase Type II - antagonists & inhibitors; omega-N-Methylarginine - pharmacology; Proteins; Public health; Rats; Rats, Wistar; Signal Transduction - drug effects; Taurochenodeoxycholic Acid - pharmacology; Transcription Factor CHOP - pharmacology; Transcription factors; Tumor Necrosis Factor-alpha - pharmacology; United States > US; ER stress; c-Jun N-terminal kinase; Human islets; Cytokines; Type 1 diabetes; Apoptosis
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-015-3669-6

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 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 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.