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

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, 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.

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

“…ER stress might contribute to the magnification of apoptotic pathways, exacerbation of inflammation and increased antigen presentation in the context of type 1 diabetes [26,37,38]. Here, we report for the first time that IFNα alone upregulates expression of several ER stress markers, including p-EIF2α, XBP1s, BIP, C/EBP homologous protein (CHOP) and ATF3.…”

“…Human islets or EndoC-βH1 cells were exposed to cytokines or other agents as described in ESM Methods [23,26].…”

“…All experiments were performed in human pancreatic islets and the human insulinproducing cell line EndoC-βH1 [24], increasing their translational potential [25][26][27][28]. The data obtained indicate that IFNα is a crucial mediator of excessive inflammation and ER stress in the early steps of type 1 diabetes.…”

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

“…JNK activity is partially responsible for downregulation of the adaptive UPR, reduced ER-to-Golgi trafficking and increased beta cell death following hypoxia JNK has been implicated in beta cell apoptosis under various stress conditions [19,[29][30][31][32][33][34]], but has not previously been investigated in the context of islet hypoxia. Here we tested whether JNK activity influences beta cell responses to hypoxia.…”

“…Although JNKi is regarded as a specific inhibitor of JNK activation, we cannot rule out the potential of an off target effect. JNK is a wellestablished stress-activated pro-apoptotic effector in beta cells [29][30][31][32][33][34]. It also plays a role in the regulation of the UPR following pro-inflammatory cytokine stimulation [19,46].…”