Inhibition of AMP-Activated Protein Kinase Protects Pancreatic β-Cells From Cytokine-Mediated Apoptosis and CD8+ T-Cell–Induced Cytotoxicity
| Autor: | Audrey Riboulet-Chavey, Frédérique Diraison, Florence Susan Wong, Lai Khai Siew, Guy A. Rutter |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Programmed cell death Cell Survival Endocrinology Diabetes and Metabolism Receptors Antigen T-Cell Apoptosis Mice Transgenic AMP-Activated Protein Kinases CD8-Positive T-Lymphocytes Protein Serine-Threonine Kinases Lymphocyte Activation Article Cell Line Mice Adenosine Triphosphate AMP-activated protein kinase Mice Inbred NOD Multienzyme Complexes Insulin-Secreting Cells Internal medicine Internal Medicine medicine Animals Cytotoxic T cell Protein kinase A NOD mice biology Pancreatic islets AMPK Recombinant Proteins Endocrinology medicine.anatomical_structure biology.protein Cancer research Cytokines |
| Zdroj: | Diabetes. 57:415-423 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db07-0993 |
| Popis: | OBJECTIVE—Apoptotic destruction of insulin-producing pancreatic β-cells is involved in the etiology of both type 1 and type 2 diabetes. AMP-activated protein kinase (AMPK) is a sensor of cellular energy charge whose sustained activation has recently been implicated in pancreatic β-cell apoptosis and in islet cell death posttransplantation. Here, we examine the importance of β-cell AMPK in cytokine-induced apoptosis and in the cytotoxic action of CD8+ T-cells. RESEARCH DESIGN AND METHODS— Clonal MIN6 β-cells or CD1 mouse pancreatic islets were infected with recombinant adenoviruses encoding enhanced green fluorescent protein (eGFP/null), constitutively active AMPK (AMPK-CA), or dominant-negative AMPK (AMPK-DN) and exposed or not to tumor necrosis factor-α, interleukin-1β, and interferon-γ. Apoptosis was detected by monitoring the cleavage of caspase-3 and DNA fragmentation. The cytotoxic effect of CD8+ purified T-cells was examined against pancreatic islets from NOD mice infected with either null or the AMPK-DN–expressing adenoviruses. RESULTS— Exposure to cytokines, or expression of AMPK-CA, induced apoptosis in clonal MIN6 β-cells and CD1 mouse pancreatic islets. By contrast, overexpression of AMPK-DN protected against the proapoptotic effect of these agents, in part by preventing decreases in cellular ATP, and lowered the cytotoxic effect of CD8+ T-cells toward NOD mouse islets. CONCLUSIONS— Inhibition of AMPK activity enhances islet survival in the face of assault by either cytokines or T-cells. AMPK may therefore represent an interesting therapeutic target to suppress immune-mediated β-cell destruction and may increase the efficacy of islet allografts in type 1 diabetes. |
| Databáze: | OpenAIRE |
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