The ToI-beta transgenic mouse: a model to study the specific role of NF-kappaB in beta-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 beta-cells. Islet infiltrating leukocytes secrete cytokines including IL-1beta and IFN-gamma, which contribute to beta-cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta-cell apoptosis. To study the role of NF-kappaB in vivo we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha) and the luciferase gene, acting specifically in beta-cells, in an inducible and reversible manner, by using the tet-on regulation system. Using this new mouse model, termed the ToI-beta mouse (for Tet-Ondelta I kappaB in beta-cells) we have previously shown in vitro, that islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-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 DeltaNIkappaBalpha transgene in the ToI-beta 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-kappaB inhibition and luciferase activity were observed. Together, our results show the ToI-beta mouse model to be a highly controlled and very accurate model for examining pancreatic beta-cell-specific temporal inhibition of NF-kappaB.