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

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

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ULB Center for Diabetes Research, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, 1070, Brussels, Belgium.
Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil.
Department of Cell and Developmental Biology, Universidade de São Paulo, São Paulo, Brazil.
ULB Center for Diabetes Research, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, 1070, Brussels, Belgium.



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.


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.


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.


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.


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

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