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

Abstract

Aims/hypothesis: IFN-γ, together with other inflammatory cytokines such as IL-1β and TNF-α, 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-γ/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≤0.05) and shorter functioning graft survival (6.0±2.6 vs 10.4±4.8 days, p≤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-3α (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. © 2009 Springer-Verlag.