BCL-6: a possible missing link for anti-inflammatory PPAR-δ signalling in pancreatic beta cells

Autor: Ronald M. Evans, Paul Hekerman, Martine I. Darville, Miriam Cnop, C.-H. Lee, Decio L. Eizirik, Ilham Kharroubi
Rok vydání: 2006
Předmět:
Zdroj: Diabetologia. 49:2350-2358
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-006-0366-5
Popis: Inflammatory mediators contribute to pancreatic beta cell death in type 1 diabetes. Beta cells respond to cytokine exposure by activating gene networks that alter cellular metabolism, induce chemokine release (thereby increasing insulitis), and cause apoptosis. We have previously shown by microarray analysis that exposure of INS-1E cells to IL-1beta + IFN-gamma induces the transcription factor peroxisome proliferator-activated receptor (Ppar)-delta and several of its target genes. PPAR-delta controls cellular lipid metabolism and is a major regulator of inflammatory responses. We therefore examined the role of PPAR-delta in cytokine-treated beta cells.Primary beta cells that had been purified by fluorescence-activated cell sorting and INS-1E cells were cultured in the presence of the cytokines TNF-alpha, IL-1beta, or IL-1beta + IFN-gamma, or the synthetic PPAR-delta agonist GW501516. Gene expression was analysed by real-time PCR. PPAR-delta, monocyte chemoattractant protein (MCP-1, now known as CCL2) promoter and NF-kappaB activity were determined by luciferase reporter assays.Exposure of primary beta cells or INS-1E cells to cytokines induced Ppar-delta mRNA expression and PPAR-delta-dependent CD36, lipoprotein lipase, acyl CoA synthetase and adipophilin mRNAs. Cytokines and the PPAR-delta agonist GW501516 also activated a PPAR-delta response element reporter in beta cells. Unlike immune cells, neither INS-1E nor beta cells expressed the transcriptional repressor B-cell lymphoma-6 (BCL-6). As a consequence, PPAR-delta activation by GW501516 did not decrease cytokine-induced Mcp-1 promoter activation or mRNA expression, as reported for macrophages. Transient transfection with a BCL-6 expression vector markedly reduced Mcp-1 promoter and NF-kappaB activities in beta cells.Cytokines activate the PPAR-delta gene network in beta cells. This network does not, however, regulate the pro-inflammatory response to cytokines because beta cells lack constitutive BCL-6 expression. This may render beta cells particularly susceptible to propagating inflammation in type 1 diabetes.
Databáze: OpenAIRE
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