title: TRAF2 mediates JNK and STAT3 activation in response to IL-1β and IFNγ and facilitates apoptotic death of insulin-producing β-cells.
abstract: Interleukin-1β (IL-1β) and interferon-γ (IFNγ) contribute to type 1 diabetes (T1D) by inducing β-cell death. Tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins are adaptors that transduce signaling from a variety of membrane receptors including cytokine receptors. We show here that IL-1β and IFNγ upregulate the expression of TRAF2 in insulin-producing INS-1E cells and isolated rat pancreatic islets. siRNA-mediated knockdown (KD) of TRAF2 in INS-1E cells reduced IL-1β-induced phosphorylation of JNK1/2, but not of p38 or ERK1/2 mitogen-activated protein kinases. TRAF2 KD did not modulate NFκB activation by cytokines, but reduced cytokine-induced inducible nitric oxide synthase (iNOS) promotor activity and expression. We further observed that IFNγ-stimulated phosphorylation of STAT3 required TRAF2. KD of TRAF2 or STAT3 reduced cytokine-induced caspase 3/7 activation, but, intriguingly, potentiated cytokine-mediated loss of plasma membrane integrity and augmented the number of propidium iodide-positive cells. Finally, we found that TRAF2 KD increased cytokine-induced production of reactive oxygen species (ROS). In summary, our data suggest that TRAF2 is an important mediator of IL-1β and IFNγ signaling in pancreatic β-cells.
authors.affiliation: Immunoendocrinology Laboratory, Endocrinology Research Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michala
authors.initials: M
authors.lastname: Prause
authors.affiliation: Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lukas Adrian
authors.initials: LA
authors.lastname: Berchtold
authors.affiliation: Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Adriana Ibarra
authors.initials: AI
authors.lastname: Urizar
authors.affiliation: Beta-Cell Biology Group, Copenhagen Diabetes Research Center, Department of Paediatrics E, Copenhagen University Hospital Herlev, Herlev, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Hyldgaard Trauelsen
authors.affiliation: Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
authors.affiliation: Immunoendocrinology Laboratory, Endocrinology Research Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.affiliation: Beta-Cell Biology Group, Copenhagen Diabetes Research Center, Department of Paediatrics E, Copenhagen University Hospital Herlev, Herlev, Denmark. Electronic address: Joachim.stoerling.01@regionh.dk.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D009336:Necrosis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D047992:TNF Receptor-Associated Factor 2; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: Apoptosis; Cytokines; STAT3; TRAF2; Type 1 diabetes; iNOS