The ToI-β transgenic mouse: a model to study the specific role of NF-κB in β-cells

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting β-cells. Islet infiltrating leukocytes secrete cytokines including IL-1β and IFN-γ, which contribute to β-cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-κB is an important component of the signal triggering β-cell apoptosis. To study the role of NF-κB in vivo we generated a transgenic mouse line expressing a degradation-resistant NF-κB protein inhibitor (ΔNIκBα) and the luciferase gene, acting specifically in β-cells, in an inducible and reversible manner, by using the tet-on reg ulation system. Using this new mouse model, termed the ToI-β mouse (for Tet-Ondelta I κB in β-cells) we have previously shown in vitro, that islets expressing the ΔNIκBα protein were resistant to the deleterious effects of IL-1β and IFN-γ, as assessed by reduced NO production and β-cell apoptosis. In vivo, a nearly complete protection against multiple low dose streptozocin-induced diabetes was observed, with reduced intra-islet lymphocytic infiltration. In the present study we demonstrate the tight regulated and reversible expression of the ΔNIκBα transgene in the ToI-β mouse model as well as the effect of its overexpression on glucose metabolism and insulin secretion. The results show a lack of effect of transgene induction on both in vivo glucose tolerance tests and in vitro islet insulin secretion and content. Furthermore, to prove the tight control of induction in the model, luciferase mediated light emission was only detected at constant levels in Dox-treated double transgenic mice or islets as well as in a model of islet transplantation. Upon removal of the inducing stimulus, complete reversal of both NF-κB inhibition and luciferase activity were observed. Together, our results show the ToI-β mouse model to be a highly controlled and very accurate model for examining pancreatic β-cell-specific temporal inhibition of NF-κB.