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Diabetologia. 2009 Nov;52(11):2374-2384. doi: 10.1007/s00125-009-1514-5. Epub 2009 Sep 8.

Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack.

Author information

1
LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium.
2
Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
3
LEGENDO, Campus Gasthuisberg O&N1, Herestraat 49, bus 902, 3000, Leuven, Belgium. chantal.mathieu@med.kuleuven.be.

Abstract

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.

PMID:
19756487
DOI:
10.1007/s00125-009-1514-5
[Indexed for MEDLINE]

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