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

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

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71 Scopus citations

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.

Original languageEnglish
Pages (from-to)1092-1101
Number of pages10
JournalDiabetologia
Volume52
Issue number6
DOIs
StatePublished - Jun 2009
Externally publishedYes

Keywords

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

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