Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

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 such as IL-1 beta and IFN-gamma, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappa B is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-kappa B in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappa B protein inhibitor (Delta IN kappa B alpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the Delta NI kappa B alpha protein were resistant to the deleterious effects of IL-1 beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-kappa B is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.