Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction
Autor: | David J. Maloney, Yumi Imai, Ganesha Rai, Theodore R. Holman, Jerry L. Nadler, Anton Simeonov, Victor Kenyon, Jessica R. Weaver, David A. Taylor-Fishwick, Ajit Jadhav |
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Rok vydání: | 2012 |
Předmět: |
endocrine system
medicine.medical_specialty Programmed cell death Interleukin-1beta Apoptosis Biology Arachidonate 12-Lipoxygenase medicine.disease_cause Biochemistry Proinflammatory cytokine Interferon-gamma Mice Onium Compounds Endocrinology Insulin-Secreting Cells Internal medicine Diabetes Mellitus medicine Animals Humans NADH NADPH Oxidoreductases Molecular Biology Chemokine CCL2 geography NADPH oxidase geography.geographical_feature_category Caspase 3 Tumor Necrosis Factor-alpha Acetophenones Islet Enzyme Activation Oxidative Stress Eicosapentaenoic Acid Lipotoxicity NADPH Oxidase 1 biology.protein Tumor necrosis factor alpha Beta cell Reactive Oxygen Species Oxidative stress |
Zdroj: | Molecular and Cellular Endocrinology. 358:88-95 |
ISSN: | 0303-7207 |
Popis: | Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p0.05), elevated expression of MCP-1 (p0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p0.01) and induction of MCP-1 (p0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes. |
Databáze: | OpenAIRE |
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