Mechanisms of IKK/NF-κB dependent diabetes development

Abstract

As a key regulator of inflammatory processes IKK/NF-κB signaling is present and activated in all cell types involved in diabetes development. However, a detailed understanding of the causal relationship between cell-type-specific NF-κB activation and onset and progression of type 1 diabetes needs further investigation. To address this issue, two complementary mouse models (gain- and loss-of-function) for IKK/NF-κB signaling were generated. Both mouse models are based on the conditional expression of mutant IKK2 alleles (constitutive active (IKK2-CA) and dominant negative (IKK2-DN)) via the tetracycline-regulated gene expression system. β-cell-specific IKK/NF-κB activation was already sufficient to initiate a full-blown immune-mediated diabetes including insulitis, hyperglycemia and hypoinsulinemia. Disease development involves a gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased MHCI/II expression. Potential novel diabetes candidate genes were also identified. Animals of the loss-of-function model also exhibit a diabetes-like phenotype characterized by a complete destruction of the islet architecture including loss of insulin content but without immune cell infiltration. Interestingly, diabetic animals of both models successfully recovered from diabetes upon transgene inactivation. Initial results indicate that this high regeneration capacity might be a consequence of dedifferentiated insulin-negative β-cells, which regain functional β-cell status upon transgene inactivation. Current work addresses the identification of molecular mechanisms involved in this kind of in vivo β-cell regeneration. For this purpose microarray based gene expression analysis was performed using islet samples that were isolated during the recovery process. Preliminary data presented on the poster suggest that autocrine/paracrine mechanisms might be involved.