PMID- 19756487
OWN - NLM
STAT- MEDLINE
DCOM- 20100426
LR  - 20211020
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 52
IP  - 11
DP  - 2009 Nov
TI  - Interferon regulatory factor-1 is a key transcription factor in murine beta cells 
      under immune attack.
PG  - 2374-2384
LID - 10.1007/s00125-009-1514-5 [doi]
AB  - AIMS/HYPOTHESIS: IFN-gamma, together with other inflammatory cytokines such as 
      IL-1beta and TNF-alpha, contributes to beta cell death in type 1 diabetes. We 
      analysed the role of the transcription factor interferon regulatory factor 
      (IRF)-1, a downstream target of IFN-gamma/signal transducer and activator of 
      transcription (STAT)-1, in immune-mediated beta cell destruction. METHODS: Islets 
      from mice lacking Irf-1 (Irf-1 (-/-)) and control C57BL/6 mice were transplanted 
      in overtly diabetic NOD mice. Viability and functionality of islets were 
      evaluated in vitro. Chemokine expression by Irf-1 (-/-) islets and INS-1E cells 
      transfected with Irf-1 short interfering RNA (siRNA) was measured by real-time 
      PCR as well as in functional assays in vitro. RESULTS: IRF-1 deletion in islets 
      was associated with higher prevalence of primary non-function (63% vs 25%, p <or= 
      0.05) and shorter functioning graft survival (6.0 +/- 2.6 vs 10.4 +/- 4.8 days, p 
      <or= 0.05) in contrast to similar skin graft survival. Although Irf-1 (-/-) 
      islets were resistant to cytokine-induced cell death, insulin secretion by them 
      was lower than that of control C57BL/6 islets under medium and cytokine 
      conditions. IL-1 receptor antagonist partly restored the cytokine-induced 
      secretory defect in vitro and completely prevented primary non-function in vivo. 
      Cytokine-exposed Irf-1 (-/-) islets and INS-1E cells transfected with Irf-1 siRNA 
      showed increased expression of Mcp-1 (also known as Ccl2), Ip-10 (also known as 
      Cxcl10), Mip-3alpha (also known as Ccl20) and Inos (also known as Nos2) mRNA and 
      elevated production of monocyte chemoattractant protein-1 (MCP-1) and nitrite 
      compared with controls. In vivo, Irf-1 (-/-) islets displayed a higher potential 
      to attract immune cells, reflected by more aggressive immune infiltration in the 
      grafted islets. CONCLUSIONS/INTERPRETATION: These data indicate a key regulatory 
      role for IRF-1 in insulin and chemokine secretion by pancreatic islets under 
      inflammatory attack.
FAU - Gysemans, C
AU  - Gysemans C
AD  - LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium.
FAU - Callewaert, H
AU  - Callewaert H
AD  - LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium.
FAU - Moore, F
AU  - Moore F
AD  - Laboratory of Experimental Medicine, Universite Libre de Bruxelles (ULB), 
      Brussels, Belgium.
FAU - Nelson-Holte, M
AU  - Nelson-Holte M
AD  - LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium.
FAU - Overbergh, L
AU  - Overbergh L
AD  - LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium.
FAU - Eizirik, D L
AU  - Eizirik DL
AD  - Laboratory of Experimental Medicine, Universite Libre de Bruxelles (ULB), 
      Brussels, Belgium.
FAU - Mathieu, C
AU  - Mathieu C
AD  - LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium. 
      chantal.mathieu@med.kuleuven.be.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090908
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (DNA Primers)
RN  - 0 (Insulin)
RN  - 0 (Interferon Regulatory Factor-1)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Transcription Factors)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Cell Death
MH  - Cell Survival
MH  - DNA Primers
MH  - Glucose/pharmacology
MH  - Graft Survival/immunology
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/cytology/immunology/*physiology
MH  - Interferon Regulatory Factor-1/deficiency/genetics/*metabolism
MH  - Islets of Langerhans Transplantation/methods
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD/surgery
MH  - Mice, Knockout
MH  - Polymerase Chain Reaction/methods
MH  - RNA, Small Interfering/genetics
MH  - Transcription Factors/*metabolism
MH  - Transfection
MH  - Transplantation, Homologous/immunology/physiology
EDAT- 2009/09/17 06:00
MHDA- 2010/04/27 06:00
CRDT- 2009/09/17 06:00
PHST- 2009/01/20 00:00 [received]
PHST- 2009/07/30 00:00 [accepted]
PHST- 2009/09/17 06:00 [entrez]
PHST- 2009/09/17 06:00 [pubmed]
PHST- 2010/04/27 06:00 [medline]
AID - 10.1007/s00125-009-1514-5 [pii]
AID - 10.1007/s00125-009-1514-5 [doi]
PST - ppublish
SO  - Diabetologia. 2009 Nov;52(11):2374-2384. doi: 10.1007/s00125-009-1514-5. Epub 
      2009 Sep 8.