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

• Published in: Diabetologia Vol. 59; no. 3; p. 512
• Main Authors: Meyerovich, Kira, Fukaya, Makiko, Terra, Leticia F, Ortis, Fernanda, Eizirik, Decio L, Cardozo, Alessandra K
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01-03-2016
• Subjects: Cell death; Cytokines; Diabetes; Genes; Kinases; Nitric oxide; Pathogenesis; Phosphorylation; Proteins; Transcription factors; Brazil
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-015-3817-z

Aims/hypothesis Activation of the transcription factor nuclear factor (NF)-[kappa]B by proinflammatory cytokines plays an important role in beta cell demise in type 1 diabetes. Two main signalling pathways are known to activate NF-[kappa]B, namely the canonical and the non-canonical pathways. Up to now, studies on the role of NF-[kappa]B 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-[kappa]B 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-[beta]H1 exposed to cytokines were used as models. Results IL-1[beta] plus IFN-γ induced stabilisation of NF-[kappa]B-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-[kappa]B-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-[kappa]B pathway by proinflammatory cytokines constitutes a novel 'feed-forward' mechanism that contributes to the particularly pro-apoptotic effect of NF-[kappa]B in beta cells.