title: The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, 1070, Brussels, Belgium.
authors.forename: Kira
authors.initials: K
authors.lastname: Meyerovich
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, 1070, Brussels, Belgium.
authors.forename: Makiko
authors.initials: M
authors.lastname: Fukaya
authors.affiliation: Institute of Chemistry, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Leticia F
authors.initials: LF
authors.lastname: Terra
authors.affiliation: Department of Cell and Developmental Biology, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ortis
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, 1070, Brussels, Belgium.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, 1070, Brussels, Belgium. akupperc@ulb.ac.be.
authors.forename: Alessandra K
authors.initials: AK
authors.lastname: Cardozo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009569:Nitric Oxide
keywords: Apoptosis; Cytokines; FBW7; FBXW7; Inflammation; Non-canonical NF-κB pathway; Pancreatic beta cell; Type 1 diabetes; βTrCP