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01.06.2009 | Article

Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

verfasst von: S. A. Sarkar, B. Kutlu, K. Velmurugan, S. Kizaka-Kondoh, C. E. Lee, R. Wong, A. Valentine, H. W. Davidson, J. C. Hutton, S. Pugazhenthi

Erschienen in: Diabetologia | Ausgabe 6/2009

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Abstract

Aims/hypothesis

The destruction of pancreatic beta cells leading to type 1 diabetes in humans is thought to occur mainly through apoptosis and necrosis induced by activated macrophages and T cells, and in which secreted cytokines play a significant role. The transcription factor nuclear factor kappa-B (NF-κB) plays an important role in mediating the apoptotic action of cytokines in beta cells. We therefore sought to determine the changes in expression of genes modulated by NF-κB in human islets exposed to a combination of IL1β, TNF-α and IFN-γ.

Methods

Microarray and gene set enrichment analysis were performed to investigate the global response of gene expression and pathways modulated in cultured human islets exposed to cytokines. Validation of a panel of NF-κB-regulated genes was performed by quantitative RT-PCR. The mechanism of induction of BIRC3 by cytokines was examined by transient transfection of BIRC3 promoter constructs linked to a luciferase gene in MIN6 cells, a mouse beta cell line.

Results

Enrichment of several metabolic and signalling pathways was observed in cytokine-treated human islets. In addition to the upregulation of known pro-apoptotic genes, a number of anti-apoptotic genes including BIRC3, BCL2A1, TNFAIP3, CFLAR and TRAF1 were induced by cytokines through NF-κB. Significant synergy between the cytokines was observed in NF-κB-mediated induction of the promoter of BIRC3 in MIN6 cells.

Conclusions/interpretation

These findings suggest that, via NF-κB activation, cytokines induce a concurrent anti-apoptotic pathway that may be critical for preserving islet integrity and viability during the progression of insulitis in type 1 diabetes.

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Titel: Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line
verfasst von: S. A. Sarkar
B. Kutlu
K. Velmurugan
S. Kizaka-Kondoh
C. E. Lee
R. Wong
A. Valentine
H. W. Davidson
J. C. Hutton
S. Pugazhenthi
Publikationsdatum: 01.06.2009
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 6/2009
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-009-1331-x

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Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

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