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*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

122 Citaten (Scopus)

Samenvatting

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)

Originele taal-2English
Pagina's (van-tot)3563-3573
Aantal pagina's11
TijdschriftBlood
Volume112
Nummer van het tijdschrift9
DOI's
StatusPublished - 1-nov-2008

Citeer dit