title: Long-term IKK2/NF-κB signaling in pancreatic β-cells induces immune-mediated diabetes.
abstract: Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic β-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 β-cells, we generated a gain-of-function model allowing conditional IKK2/NF-κB activation in β-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 β-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 β-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 β-cell degeneration/regeneration.
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Ulm, Germany.
authors.forename: Heba H
authors.initials: HH
authors.lastname: Salem
authors.forename: Bernadette
authors.initials: B
authors.lastname: Trojanowski
authors.forename: Katja
authors.initials: K
authors.lastname: Fiedler
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Maier
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
mesh_terms: D000818:Animals; D017209:Apoptosis; D054414:Chemokine CCL17 / Q000502:physiology; D054422:Chemokine CCL22 / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D059865:Endoplasmic Reticulum Stress; D018398:Homeodomain Proteins / Q000235:genetics; D051550:I-kappa B Kinase / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics; D059467:Transcriptome
chemical_list: C499538:Ccl17 protein, mouse; C515483:Ccl22 protein, mouse; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D018398:Homeodomain Proteins; D016328:NF-kappa B; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse