Journal
DIABETOLOGIA
Volume 52, Issue 6, Pages 1092-1101Publisher
SPRINGER
DOI: 10.1007/s00125-009-1331-x
Keywords
Apoptosis; BIRC3; Cytokines; Human islets; Microarray; NF-kappa B; Type 1 diabetes
Categories
Funding
- Juvenile Diabetes Research Foundation [5-2005-1104, 02-05-60294, 1-2008-1021]
- American Diabetes Association [1-06-JF-40]
- NIH/NIDDK [K01 DK080193]
- NIDDK/DERC
- University of Colorado Denver [NIH 5 U42 RR016599]
- NIH/NIDDK/JDRF
- DERC Molecular and Bioinformatics core facilities [NIH P30 DK57516]
Ask authors/readers for more resources
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-kappa B) 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-kappa B in human islets exposed to a combination of IL1 beta, TNF-alpha and IFN-gamma. 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-kappa B-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. 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-kappa B. Significant synergy between the cytokines was observed in NF-kappa B-mediated induction of the promoter of BIRC3 in MIN6 cells. These findings suggest that, via NF-kappa B 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available