Submitted March 11, 2008
Accepted July 23, 2008
HMG-CoA reductase inhibition induces IL-1
release through Rac1/PI3K/PKB-dependent caspase-1 activation
Loes M. Kuijk, Jeffrey M. Beekman, Janet Koster, Hans R. Waterham, Joost Frenkel, and Paul J. Coffer*
Department of General Pediatrics, University Medical Centre, Utrecht, Netherlands
Department of Pediatric Immunology, University Medical Centre, Utrecht, Netherlands
Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Academic Medical Centre, Amsterdam, Netherlands
Molecular Immunology Lab, Department of Immunology, University Medical Centre, Utrecht, Netherlands
* Corresponding author; email: p.j.coffer{at}umcutrecht.nl.
Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis. LPS-stimulated peripheral blood mononuclear cells (PBMC) from MKD patients secrete high levels of IL-1
, due to 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 secretion in a Rac1/PI3K-dependent manner. Simvastatin treatment was found to activate PKB/c-akt, a primary effector of PI3K, and ectopic expression of constitutively active PKB was sufficient to induce IL-1 release. The small GTPase Rac1 was also found to be activated by simvastatin and this was required for both PKB activation and IL-1 secretion. IL-1 release is dependent on processing 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 processing and release. Importantly, inhibition of Rac1 in PBMC isolated from MKD patients resulted in a dramatic reduction in IL-1 release. These data suggest that pharmacological inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD.
