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

Author(s)

Meyerovich, Kira ^[1] ; Fukaya, Makiko ^[1] ; Terra, Leticia F. ^[2] ; Ortis, Fernanda ^[3] ; Eizirik, Decio L. ^[1] ; Cardozo, Alessandra K. ^[1]

Affiliation

^[1] Univ Libre Bruxelles, ULB Ctr Diabet Res, Route Lennik 808, CP 618, B-1070 Brussels - Belgium

^[2] Univ Sao Paulo, Inst Chem, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Cell & Dev Biol, Sao Paulo - Brazil

• Document type: Journal article
• Source: Diabetologia; v. 59, n. 3, p. 512-521, MAR 2016.
• Web of Science Citations: 9

Abstract

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-kappa induced stabilisation of NF-kappa Binducing 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-beta 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. (AU)

• FAPESP's process: 10/05587-1 - Study of the differential NF-kB activation in beta cells and the mechanisms that can be modulated for the prevention of its pro-apoptotic effect
• Grantee: Fernanda Ortis
• Support Opportunities: Research Grants - Young Investigators Grants