PMID- 26610752
OWN - NLM
STAT- MEDLINE
DCOM- 20160930
LR  - 20160106
IS  - 1872-8057 (Electronic)
IS  - 0303-7207 (Linking)
VI  - 420
DP  - 2016 Jan 15
TI  - TRAF2 mediates JNK and STAT3 activation in response to IL-1beta and IFNgamma and 
      facilitates apoptotic death of insulin-producing beta-cells.
PG  - 24-36
LID - S0303-7207(15)30146-5 [pii]
LID - 10.1016/j.mce.2015.11.021 [doi]
AB  - Interleukin-1beta (IL-1beta) and interferon-gamma (IFNgamma) contribute to type 1 diabetes 
      (T1D) by inducing beta-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-1beta and IFNgamma 
      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-1beta-induced phosphorylation of JNK1/2, but not of p38 or ERK1/2 
      mitogen-activated protein kinases. TRAF2 KD did not modulate NFkappaB activation by 
      cytokines, but reduced cytokine-induced inducible nitric oxide synthase (iNOS) 
      promotor activity and expression. We further observed that IFNgamma-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-1beta and IFNgamma signaling in 
      pancreatic beta-cells.
CI  - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved.
FAU - Prause, Michala
AU  - Prause M
AD  - 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.
FAU - Berchtold, Lukas Adrian
AU  - Berchtold LA
AD  - Section of Cellular and Metabolic Research, Department of Biomedical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Urizar, Adriana Ibarra
AU  - Urizar AI
AD  - Section of Cellular and Metabolic Research, Department of Biomedical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Hyldgaard Trauelsen, Mette
AU  - Hyldgaard Trauelsen M
AD  - Beta-Cell Biology Group, Copenhagen Diabetes Research Center, Department of 
      Paediatrics E, Copenhagen University Hospital Herlev, Herlev, Denmark.
FAU - Billestrup, Nils
AU  - Billestrup N
AD  - Section of Cellular and Metabolic Research, Department of Biomedical Sciences, 
      University of Copenhagen, Copenhagen, Denmark.
FAU - Mandrup-Poulsen, Thomas
AU  - Mandrup-Poulsen T
AD  - Immunoendocrinology Laboratory, Endocrinology Research Section, Department of 
      Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Storling, Joachim
AU  - Storling J
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151122
PL  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspases/metabolism
MH  - Cell Line
MH  - Enzyme Activation/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Inflammation Mediators/pharmacology
MH  - Insulin-Secreting Cells/*cytology/drug effects/metabolism
MH  - Interferon-gamma/*pharmacology
MH  - Interleukin-1beta/*pharmacology
MH  - JNK Mitogen-Activated Protein Kinases/*metabolism
MH  - Mice
MH  - Necrosis
MH  - Nitric Oxide Synthase Type II/metabolism
MH  - Phosphorylation/drug effects
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
MH  - STAT3 Transcription Factor/*metabolism
MH  - TNF Receptor-Associated Factor 2/*metabolism
MH  - Up-Regulation/drug effects
OTO - NOTNLM
OT  - Apoptosis
OT  - Cytokines
OT  - STAT3
OT  - TRAF2
OT  - Type 1 diabetes
OT  - iNOS
EDAT- 2015/11/28 06:00
MHDA- 2016/10/01 06:00
CRDT- 2015/11/28 06:00
PHST- 2015/08/05 00:00 [received]
PHST- 2015/11/16 00:00 [revised]
PHST- 2015/11/16 00:00 [accepted]
PHST- 2015/11/28 06:00 [entrez]
PHST- 2015/11/28 06:00 [pubmed]
PHST- 2016/10/01 06:00 [medline]
AID - S0303-7207(15)30146-5 [pii]
AID - 10.1016/j.mce.2015.11.021 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 2016 Jan 15;420:24-36. doi: 10.1016/j.mce.2015.11.021. Epub 
      2015 Nov 22.