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

• Published in: Diabetologia 2009-06, Vol.52 (6), p.1092-1101
• Main Authors: Sarkar, S. A, Kutlu, B, Velmurugan, K, Kizaka-Kondoh, S, Lee, C. E, Wong, R, Valentine, A, Davidson, H. W, Hutton, J. C, Pugazhenthi, S
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein; Biological and medical sciences; BIRC3; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; Cell Line; Cells; Cells, Cultured; Cytokines; Cytokines - pharmacology; Diabetes; Diabetes. Impaired glucose tolerance; DNA-Binding Proteins - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene expression; Human islets; Human Physiology; Humans; Inhibitor of Apoptosis Proteins - genetics; insulin-dependent diabetes mellitus; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Interferon-gamma - pharmacology; Interleukin-1beta - pharmacology; Internal Medicine; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Kinases; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Microarray; Minor Histocompatibility Antigens; NF-kappa B - metabolism; NF-κB; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-bcl-2 - genetics; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; TNF Receptor-Associated Factor 1 - genetics; Transcription factors; Tumor Necrosis Factor-alpha - pharmacology; Ubiquitin-Protein Ligases
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-009-1331-x

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.