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; Pirot, P.; Naamane, N.; Kreins, Alexandra Yema; Rasschaert, J.; Moore, F.; Theatre, Emilie; Verhaeghe, Catherine; Magnusson, N. E.; Chariot, Alain; Orntoft, T. F.; Eizirik, Decio L

doi:10.1007/s00125-008-0999-7

Article (Scientific journals)

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; Pirot, P.; Naamane, N. et al.

2008 • In Diabetologia, 51, p. 1213-1225

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/1382

DOI
10.1007/s00125-008-0999-7

PubMed
18463842

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Keywords :

NF kappa B; IL-1; pancreas

Abstract :

[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.

Research Center/Unit :

Giga-Signal Transduction - ULiège

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Ortis, Fernanda; Université Libre de Bruxelles - ULB > Laboratory of Experimental Medicine

Pirot, P.; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine

Naamane, N.; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Kreins, Alexandra Yema

Rasschaert, J.

Moore, F.

Theatre, Emilie

Verhaeghe, Catherine

Magnusson, N. E.

Chariot, Alain

Orntoft, T. F.

Eizirik, Decio L

Language :

English

Title :

Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells

Publication date :

July 2008

Journal title :

Diabetologia

ISSN :

0012-186X

eISSN :

1432-0428

Publisher :

Springer Verlag, Berlin, Germany

Volume :

Pages :

1213-1225

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique

Available on ORBi :

since 27 November 2008

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