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


ABSTRACT: 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-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 in vivo role of NF-kappaB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, 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. 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-kappaB 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.

SUBMITTER: Eldor R 

PROVIDER: S-EPMC1458796 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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

Eldor R R   Yeffet A A   Baum K K   Doviner V V   Amar D D   Ben-Neriah Y Y   Christofori G G   Peled A A   Carel J C JC   Boitard C C   Klein T T   Serup P P   Eizirik D L DL   Melloul D D  

Proceedings of the National Academy of Sciences of the United States of America 20060321 13


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-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  ...[more]

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