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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

216 Scopus citations

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. Isletinfiltrating leukocytes secrete cytokines such as IL-1β and IFN-γ, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-κB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-κB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the ΔNIκBα protein were resistant to the deleterious effects of IL-1β and IFN-γ, 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-κB 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.

Original languageAmerican English
Pages (from-to)5072-5077
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number13
DOIs
StatePublished - 28 Mar 2006

Keywords

  • Apoptosis
  • Cytokine
  • Diabetes transgenic mice
  • Insulin

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