title: Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Flora
authors.initials: F
authors.lastname: Brozzi
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Tarlliza R
authors.initials: TR
authors.lastname: Nardelli
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lopes
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Millard
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Jenny
authors.initials: J
authors.lastname: Barthson
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Mariana
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Grieco
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Olatz
authors.initials: O
authors.lastname: Villate
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Oliveira
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium.
authors.forename: Marina
authors.initials: M
authors.lastname: Casimir
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Laboratory, University of Pisa, Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.affiliation: Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, 53706, USA.
authors.forename: Feyza
authors.initials: F
authors.lastname: Engin
authors.affiliation: Department of Genetics and Complex Diseases, Sabri Ülker Center, Harvard School of Public Health, Boston, MA, 02115, USA.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Laboratory, University of Pisa, Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: ULB-Center for Diabetes Research, Universitè Libre de Bruxelles (ULB), Route de Lennik, 808-CP618, 1070, Brussels, Belgium. deizirik@ulb.ac.be.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D051742:Transcription Factor CHOP; D019323:omega-N-Methylarginine; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II
keywords: Apoptosis; Cytokines; ER stress; Human islets; Type 1 diabetes; c-Jun N-terminal kinase