Blood Journal
Leading the way in experimental and clinical research in hematology

HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation

  1. Loes M. Kuijk1,2,
  2. Jeffrey M. Beekman2,
  3. Janet Koster3,
  4. Hans R. Waterham3,
  5. Joost Frenkel1, and
  6. Paul J. Coffer2,4
  1. Departments of 1General Pediatrics and
  2. 2Pediatric Immunology, University Medical Centre, Utrecht;
  3. 3Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam; and
  4. 4Molecular Immunology Lab, Department of Immunology, University Medical Centre, Utrecht, The Netherlands

Abstract

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-1β (IL-1β) 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-1β 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-1β release. The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1β secretion. IL-1β 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-1β release. Importantly, inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL-1β release. These data suggest that pharmacologic inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD.

  • Submitted March 11, 2008.
  • Accepted July 23, 2008.
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