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STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation.

ABSTRACT: Cytokines produced by islet-infiltrating immune cells induce ?-cell apoptosis in type 1 diabetes. The IFN-?-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on ?-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in ?-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1? and IFN-?. Relevant microarray findings were further studied in INS-1E cells and primary rat ?-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated ?-cell phenotype, as indicated by decreased insulin, Pdx1, MafA, and Glut2. Furthermore, STAT1 regulates cytokine-induced apoptosis via up-regulation of the proapoptotic protein DP5. STAT1 and IRF-1 have opposite effects on cytokine-induced chemokine production, with IRF-1 exerting negative feedback inhibition on STAT1 and downstream chemokine expression. The present study elucidates the transcriptional networks through which the IFN-?/STAT1/IRF-1 axis controls ?-cell function/differentiation, demise, and islet inflammation.

SUBMITTER: Moore F

PROVIDER: S-EPMC3020778 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation.

Moore Fabrice F Naamane Najib N Colli Maikel L ML Bouckenooghe Thomas T Ortis Fernanda F Gurzov Esteban N EN Igoillo-Esteve Mariana M Mathieu Chantal C Bontempi Gianluca G Thykjaer Thomas T Ørntoft Torben F TF Eizirik Decio L DL

The Journal of biological chemistry 20101027 2

Cytokines produced by islet-infiltrating immune cells induce β-cell apoptosis in type 1 diabetes. The IFN-γ-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on β-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in β-cells. Thi ...[more]

PMID: 20980260

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Project description:Aims/Hypothesis: Galectin 3 appears to play a proinflammatory role in several inflammatory and autoimmune diseases. Also, there is evidence that galectin 3 plays a role in both type-1 and type-2 diabetes. During obesity, hematopoietic cell-derived galectin 3 induces insulin resistance. While the role of galectin 3 expressed in islet-invading immune cells in both type-1 and type-2 diabetes has been studied, the importance of the expression of this molecule on the target pancreatic β cells has not been defined. Methods: To clarify the role of galectin 3 expression in β cells during obesity-induced diabetogenesis, we developed transgenic mice selectively overexpressing galectin 3 in β cells and tested their susceptibility to obesity-induced type-2 diabetes. Obesity was induced with a 16-week high-fat diet regime. Pancreatic β cells were tested for susceptibility to apoptosis induced by non-esterified fatty acids and cytokines as well as parameters of oxidative stress. Results: Our results demonstrated that overexpression of galectin 3 increases β-cell apoptosis in HFD conditions and increases the percentage of proinflammatory F4/80+ macrophages in islets that express galectin 3 and TLR4. In isolated islets, we have shown that galectin 3 overexpression increases cytokine and palmitate-triggered β-cell apoptosis and also increases NO2--induced oxidative stress of β cells. Also, in pancreatic lymph nodes, macrophages were shifted toward a proinflammatory TNF-α-producing phenotype. Conclusions/Interpretation: By complementary in vivo and in vitro approaches, we have shown that galectin 3-overexpression facilitates β-cell damage, enhances cytokine and palmitate-triggered β-cell apoptosis, and increases NO2--induced oxidative stress in β cells. Further, the results suggest that increased expression of galectin 3 in the pancreatic β cells affects the metabolism of glucose and glycoregulation in mice on a high-fat diet, affecting both fasting glycemic values and glycemia after glucose loading.

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STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation.

Publications

STAT1 is a master regulator of pancreatic {beta}-cell apoptosis and islet inflammation.

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