Reference : Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells
Ortis, Fernanda [Université Libre de Bruxelles - ULB > Laboratory of Experimental Medicine >]
Pirot, P. [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Génétique générale et humaine >]
Naamane, N. [Université de Liège - ULg > Département de pharmacie > Chimie médicale >]
Kreins, Alexandra Yema [> > > >]
Rasschaert, J. [> > > >]
Moore, F. [> > > >]
Theatre, Emilie [> > > >]
Verhaeghe, Catherine [> > > >]
Magnusson, N. E. [> > > >]
Chariot, Alain mailto [> > > >]
Orntoft, T. F. [> > > >]
Eizirik, Decio L [> > > >]
Springer Verlag
Yes (verified by ORBi)
[en] NF kappa B ; IL-1 ; pancreas
[en] IL-1beta and TNF-alpha contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-kappaB (NF-kappaB), but recent observations suggest that NF-kappaB blockade prevents IL-1beta + IFN-gamma- but not TNF-alpha + IFN-gamma-induced beta cell apoptosis. The aim of the present study was to compare the effects of IL-1beta and TNF-alpha on cell death and the pattern of NF-kappaB activation and global gene expression in beta cells. METHODS: Cell viability was measured after exposure to IL-1beta or to TNF-alpha alone or in combination with IFN-gamma, and blockade of NF-kappaB activation or protein synthesis. INS-1E cells exposed to IL-1beta or TNF-alpha in time course experiments were used for IkappaB kinase (IKK) activation assay, detection of p65 NF-kappaB by immunocytochemistry, real-time RT-PCR and microarray analysis. RESULTS: Blocking NF-kappaB activation protected beta cells against IL-1beta + IFNgamma- or TNFalpha + IFNgamma-induced apoptosis. Blocking de novo protein synthesis did not increase TNF-alpha- or IL-1beta-induced beta cell death, in line with the observations that cytokines induced the expression of the anti-apoptotic genes A20, Iap-2 and Xiap to a similar extent. Microarray analysis of INS-1E cells treated with IL-1beta or TNF-alpha showed similar patterns of gene expression. IL-1beta, however, induced a higher rate of expression of NF-kappaB target genes putatively involved in beta cell dysfunction and death and a stronger activation of the IKK complex, leading to an earlier translocation of NF-kappaB to the nucleus. CONCLUSIONS/INTERPRETATION: NF-kappaB activation in beta cells has a pro-apoptotic role following exposure not only to IL-1beta but also to TNF-alpha. The more marked beta cell death induced by IL-1beta is explained at least in part by higher intensity NF-kappaB activation, leading to increased transcription of key target genes.
Giga-Signal Transduction
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS
Researchers ; Professionals ; Students

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