Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack
| Autor: | Cécile Mathieu, Hanne Callewaert, Lutgart Overbergh, Decio L. Eizirik, Molly Nelson-Holte, Fabrice Moore, Conny Gysemans |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Cell Survival Endocrinology Diabetes and Metabolism Islets of Langerhans Transplantation Biology Transfection Polymerase Chain Reaction Mice Mice Inbred NOD Insulin-Secreting Cells Internal medicine Insulin Secretion Internal Medicine medicine Animals Insulin Transplantation Homologous CXCL10 RNA Small Interfering STAT4 DNA Primers NOD mice Mice Knockout Cell Death Pancreatic islets Graft Survival Mice Inbred C57BL Glucose Endocrinology medicine.anatomical_structure IRF1 Chemokine secretion IRF8 Beta cell Interferon Regulatory Factor-1 Transcription Factors |
| Zdroj: | Diabetologia. 52:2374-2384 |
| ISSN: | 1432-0428 0012-186X |
| DOI: | 10.1007/s00125-009-1514-5 |
| Popis: | 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. 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. 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. These data indicate a key regulatory role for IRF-1 in insulin and chemokine secretion by pancreatic islets under inflammatory attack. |
| Databáze: | OpenAIRE |
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