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Diabetes 54:452-461, 2005
© 2005 by the American Diabetes Association, Inc.

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

Alessandra K. Cardozo1, Fernanda Ortis1, Joachim Storling2, Ying-Mei Feng1, Joanne Rasschaert1, Morten Tonnesen2, Françoise Van Eylen3, Thomas Mandrup-Poulsen2,4, André Herchuelz2, and Décio L. Eizirik1

1 Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
2 Steno Diabetes Center, Gentofte, Denmark
3 Laboratory of Pharmacology, Université Libre de Bruxelles, Brussels, Belgium
4 Department of Molecular Medicine, Karoliska Institute, Stockholm, Sweden

Cytokines and free radicals are mediators of ß-cell death in type 1 diabetes. Under in vitro conditions, interleukin-1ß (IL-1ß) + {gamma}-interferon (IFN-{gamma}) induce nitric oxide (NO) production and apoptosis in rodent and human pancreatic ß-cells. We have previously shown, by microarray analysis of primary ß-cells, that IL-1ß + IFN-{gamma} decrease expression of the mRNA encoding for the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b (SERCA2b) while inducing expression of the endoplasmic reticulum stress–related and proapoptotic gene CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). In the present study we show that cytokine-induced apoptosis and necrosis in primary rat ß-cells and INS-1E cells largely depends on NO production. IL-1ß + IFN-{gamma}, via NO synthesis, markedly decreased SERCA2b protein expression and depleted ER Ca2+ stores. Of note, ß-cells showed marked sensitivity to apoptosis induced by SERCA blockers, as compared with fibroblasts. Cytokine-induced ER Ca2+ depletion was paralleled by an NO-dependent induction of CHOP protein and activation of diverse components of the ER stress response, including activation of inositol-requiring ER-to-nucleus signal kinase 1{alpha} (IRE1{alpha}) and PRK (RNA-dependent protein kinase)-like ER kinase (PERK)/activating transcription factor 4 (ATF4), but not ATF6. In contrast, the ER stress–inducing agent thapsigargin triggered these four pathways in parallel. In conclusion, our results suggest that the IL-1ß + IFN-{gamma}–induced decrease in SERCA2b expression, with subsequent depletion of ER Ca2+ and activation of the ER stress pathway, is a potential contributory mechanism to ß-cell death.

Address correspondence and reprint requests to Dr. Alessandra K. Cardozo Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808 CP-618, 1070 Brussels, Belgium. E-mail: akupperc{at}ulb.ac.be

Abbreviations: ATF, activating transcription factor; BiP, immunoglobulin heavy-chain binding protein; [Ca2+]i, intracellular Ca2+ concentration; CHOP, C/EBP (CCAAT/enhancer binding protein) homologous protein; CPA, cyclopiazonic acid; eIF2{alpha}, eukaryotic translation initiation factor 2{alpha}; ER, endoplasmic reticulum; FACS, fluorescence-activated cell sorting; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN-{gamma}, {gamma}-interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IRE1{alpha}, inositol-requiring ER-to-nucleus signal kinase 1{alpha}; JNK, c-Jun NH2-terminal kinase; LMA, NG-methyl-L-arginine; PERK, PRK (RNA-dependent protein kinase)-like ER kinase; SERCA, sarcoendoplasmic reticulum Ca2+ ATPase; xbp-1, X-box binding protein-1


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