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PMID:11687580

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Citation

Cardozo, AK, Heimberg, H, Heremans, Y, Leeman, R, Kutlu, B, Kruhøffer, M, Ørntoft, T and Eizirik, DL (2001) A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells. J. Biol. Chem. 276:48879-86

Abstract

Type 1 diabetes mellitus results from an autoimmune destruction of pancreatic beta-cells. Cytokines, such as interleukin-1 beta and interferon-gamma, are putative mediators of immune-induced beta-cell death and, under in vitro conditions, cause beta-cell apoptosis. We have recently shown that interleukin-1 beta + interferon-gamma modifies the expression of >200 genes in beta-cells. Several of these genes are putative targets for the transcription factor nuclear factor-kappa B (NF-kappa B), and in subsequent experiments we showed that NF-kappa B activation is mostly pro-apoptotic in beta-cells. To identify cytokine-induced and NF-kappa B-regulated genes in primary rat beta-cells, we presently combined two experimental approaches: 1) blocking of NF-kappa B activation in cytokine-exposed beta-cells by a recombinant adenovirus (AdI kappa B((SA)2)) containing an inhibitor of NF-kappa B alpha (I kappa Bac) super-repressor (S32A/S36A) and 2) study of gene expression by microarray analysis. We identified 66 cytokine-modified and NF-kappa B-regulated genes in beta-cells. Cytokine-induced NF-kappa B activation decreased Pdx-1 and increased c-Myc expression. This, together with NF-kappa B-dependent inhibition of Glut-2, pro-hormone convertase-1, and Isl-1 expression, probably contributes to the loss of differentiated beta-cell functions. NF-kappa B also regulates several genes encoding for chemokines and cytokines in beta-cells. The present data suggest that NF-kappa B is a key "switch regulator" of transcription factors and gene networks controlling cytokine-induced beta-cell dysfunction and death.

Links

PubMed Online version:10.1074/jbc.M108658200

Keywords

Adenoviridae/genetics; Adenoviridae/metabolism; Animals; Cells, Cultured; Cytokines/pharmacology; Diabetes Mellitus, Type 1/immunology; Diabetes Mellitus, Type 1/physiopathology; Gene Expression Regulation; I-kappa B Proteins/genetics; Islets of Langerhans/drug effects; Islets of Langerhans/physiology; Male; Models, Biological; NF-kappa B/antagonists & inhibitors; NF-kappa B/metabolism; NF-kappa B/pharmacology; Nitric Oxide/metabolism; Nitric Oxide Synthase/genetics; Nitric Oxide Synthase/metabolism; Nitric Oxide Synthase Type II; Oligonucleotide Array Sequence Analysis; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:MYC

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

RAT:MYC

involved_in

GO:0071345: cellular response to cytokine stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PDX1

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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