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

2008

AIMS/HYPOTHESIS: 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.
Journal Article
Research Support, Non-U.S. Gov't
info:eu-repo/semantics/published

Sciences bio-médicales et agricoles; Animals; Apoptosis -- drug effects; Apoptosis -- physiology; Cell Nucleus -- metabolism; Cells, Cultured; Diabetes Mellitus, Type 1 -- immunology; Diabetes Mellitus, Type 1 -- pathology; Diabetes Mellitus, Type 1 -- physiopathology; Gene Expression Profiling; Gene Expression Regulation -- drug effects; Gene Expression Regulation -- immunology; I-kappa B Kinase -- metabolism; Insulin-Secreting Cells -- cytology; Insulin-Secreting Cells -- drug effects; Insulin-Secreting Cells -- physiology; Interleukin-1beta -- metabolism; Interleukin-1beta -- pharmacology; NF-kappa B -- genetics; NF-kappa B -- metabolism; Oligonucleotide Array Sequence Analysis; Rats; Rats, Wistar; Signal Transduction -- drug effects; Signal Transduction -- immunology; Tumor Necrosis Factor-alpha -- metabolism; Tumor Necrosis Factor-alpha -- pharmacology; Apoptosis; Diabetes mellitus; Pancreatic beta cells; info:eu-repo/semantics/article; info:ulb-repo/semantics/articlePeerReview; info:ulb-repo/semantics/openurl/article

Open access content. Open access content
1 full-text file(s): info:eu-repo/semantics/restrictedAccess

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English

EQY oai:dipot.ulb.ac.be:2013/52504
uri/info:doi/10.1007/s00125-008-0999-7
uri/info:pmid/18463842
uri/info:scp/44749083828
764587682

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