The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro

Diabetologia. 2016 Mar;59(3):512-21. doi: 10.1007/s00125-015-3817-z. Epub 2015 Dec 3.


Aims/hypothesis: Activation of the transcription factor nuclear factor (NF)-κB by proinflammatory cytokines plays an important role in beta cell demise in type 1 diabetes. Two main signalling pathways are known to activate NF-κB, namely the canonical and the non-canonical pathways. Up to now, studies on the role of NF-κB activation in beta cells have focused on the canonical pathway. The aim of this study was to investigate whether cytokines activate the non-canonical pathway in beta cells, how this pathway is regulated and the consequences of its activation on beta cell fate.

Methods: NF-κB signalling was analysed by immunoblotting, promoter reporter assays and real-time RT-PCR, after knockdown or overexpression of key genes/proteins. INS-1E cells, FACS-purified rat beta cells and the human beta cell line EndoC-βH1 exposed to cytokines were used as models.

Results: IL-1β plus IFN-γ induced stabilisation of NF-κB-inducing kinase and increased the expression and cleavage of p100 protein, culminating in the nuclear translocation of p52, the hallmark of the non-canonical signalling. This activation relied on different crosstalks between the canonical and non-canonical pathways, some of which were beta cell specific. Importantly, cytokine-mediated activation of the non-canonical pathway controlled the expression of 'late' NF-κB-dependent genes, regulating both pro-apoptotic and inflammatory responses, which are implicated in beta cell loss in early type 1 diabetes.

Conclusions/interpretation: The atypical activation of the non-canonical NF-κB pathway by proinflammatory cytokines constitutes a novel 'feed-forward' mechanism that contributes to the particularly pro-apoptotic effect of NF-κB in beta cells.

Keywords: Apoptosis; Cytokines; FBW7; FBXW7; Inflammation; Non-canonical NF-κB pathway; Pancreatic beta cell; Type 1 diabetes; βTrCP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cytokines / pharmacology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Humans
  • Immunoprecipitation
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • NF-kappa B / metabolism*
  • Nitric Oxide / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects


  • Cytokines
  • NF-kappa B
  • Nitric Oxide