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.
Keywords Apoptosis - BIRC3 - Cytokines - Human islets - Microarray - NF-κB - Type 1 diabetes