| First Author | Salem HH | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 3 | Pages | 960-75 |
| PubMed ID | 24296718 | Mgi Jnum | J:209076 |
| Mgi Id | MGI:5565638 | Doi | 10.2337/db13-1037 |
| Citation | Salem HH, et al. (2014) Long-term IKK2/NF-kappaB signaling in pancreatic beta-cells induces immune-mediated diabetes. Diabetes 63(3):960-75 |
| abstractText | Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic beta-cells initiated by yet unknown factors. Although animal models of type 1 diabetes have substantially increased our understanding of disease pathogenesis, heterogeneity seen in human patients cannot be reflected by a single model and calls for additional models covering different aspects of human pathophysiology. Inhibitor of kappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) signaling is a master regulator of inflammation; however, its role in diabetes pathogenesis is controversially discussed by studies using different inhibition approaches. To investigate the potential diabetogenic effects of NF-kappaB in beta-cells, we generated a gain-of-function model allowing conditional IKK2/NF-kappaB activation in beta-cells. A transgenic mouse model that expresses a constitutively active mutant of human IKK2 dependent on Pdx-1 promoter activity (IKK2-CA(Pdx-1)) spontaneously develops full-blown immune-mediated diabetes with insulitis, hyperglycemia, and hypoinsulinemia. Disease development involves a gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased major histocompatibility complex class I/II expression by beta-cells that could collectively promote diabetes development. Potential novel diabetes candidate genes were also identified. Interestingly, animals successfully recovered from diabetes upon transgene inactivation. Our data give the first direct evidence that beta-cell-specific IKK2/NF-kappaB activation is a potential trigger of immune-mediated diabetes. Moreover, IKK2-CA(Pdx-1) mice provide a novel tool for studying critical checkpoints in diabetes pathogenesis and mechanisms governing beta-cell degeneration/regeneration. |
