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
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
DOI: 10.1182/blood-2008-03-144667
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