HMG-CoA reductase inhibition induces IL-1 beta release through Rac1/PI3K/PKB-dependent caspase-1 activation
| Autor: | Joost Frenkel, Loes M. Kuijk, Janet Koster, Paul J. Coffer, Hans R. Waterham, Jeffrey M. Beekman |
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| Přispěvatelé: | Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, University of Groningen |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
rac1 GTP-Binding Protein medicine.medical_specialty Simvastatin MEVALONATE KINASE-DEFICIENCY HYPERIMMUNOGLOBULINEMIA-D Immunology Interleukin-1beta Pharmacology Biochemistry Peripheral blood mononuclear cell p38 Mitogen-Activated Protein Kinases Cell Line PATHWAY Phosphatidylinositol 3-Kinases Internal medicine medicine Humans INTERLEUKIN-1-BETA SECRETION PHOSPHORYLATION Protein kinase B PROTEIN ISOPRENYLATION DNA Primers GENE-EXPRESSION Mevalonate kinase deficiency biology Base Sequence Caspase 1 NF-kappa B Mevalonate kinase Cell Biology Hematology medicine.disease Hydroxymethylglutaryl-CoA reductase Interleukin-1 beta secretion Enzyme Activation Endocrinology PERIODIC FEVER SYNDROME MURINE MACROPHAGES HMG-CoA reductase CELLS biology.protein Hydroxymethylglutaryl-CoA Reductase Inhibitors Mevalonate Kinase Deficiency Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Blood, 112(9), 3563. American Society of Hematology Blood, 112(9), 3563-3573. American Society of Hematology Blood, 112(9), 3563-3573. AMER SOC HEMATOLOGY |
| ISSN: | 0006-4971 3563-3573 |
| Popis: | Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin-1 beta (IL-1 beta) because of the presence of hyperactive caspase-1, and this has been proposed to be the primary cause of recurring inflammation. Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1 beta secretion in a Rac1/PI3K-dependent manner. Simvastatin treatment was found to activate protein kinase B (PKB)/c-akt, a primary effector of PI3K, and ectopic expression of constitutively active PKB was sufficient to induce IL-1 beta release. The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1 beta secretion. IL-1 beta release is mediated by caspase-1, and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K-dependent manner. These data suggest that, in MKD, dysregulated isoprenoid biosynthesis activates Rac1/PI3K/PKB, resulting in caspase-1 activation with increased IL-1 beta release. Importantly, inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL-1 beta release. These data suggest that pharmacologic inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD. (Blood. 2008; 112: 3563-3573) |
| Databáze: | OpenAIRE |
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