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

Loes M. Kuijk, Jeffrey M. Beekman, Janet Koster, Hans R. Waterham, Joost Frenkel, Paul J. Coffer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

119 Citations (Scopus)

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-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)

Original languageEnglish
Pages (from-to)3563-3573
Number of pages11
JournalBlood
Volume112
Issue number9
DOIs
Publication statusPublished - 1-Nov-2008

Keywords

  • PERIODIC FEVER SYNDROME
  • MEVALONATE KINASE-DEFICIENCY
  • HYPERIMMUNOGLOBULINEMIA-D
  • PROTEIN ISOPRENYLATION
  • GENE-EXPRESSION
  • INTERLEUKIN-1-BETA SECRETION
  • MURINE MACROPHAGES
  • CELLS
  • PHOSPHORYLATION
  • PATHWAY

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