Long-term IKK2/NF-κB signaling in pancreatic ß-cells induces immune-mediated diabetes.
Diabetes
; 63(3): 960-75, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24296718
ABSTRACT
Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic ß-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 κB kinase (IKK)/nuclear factor-κB (NF-κB) 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-κB in ß-cells, we generated a gain-of-function model allowing conditional IKK2/NF-κB activation in ß-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 ß-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 ß-cell-specific IKK2/NF-κB 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 ß-cell degeneration/regeneration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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NF-kappa B
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Diabetes Mellitus Tipo 1
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Células Secretoras de Insulina
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Quinase I-kappa B
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Alemanha