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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3563-3573. Prepublished online as a Blood First Edition Paper on August 6, 2008; DOI 10.1182/blood-2008-03-144667. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-03-144667v1 112/9/3563    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuijk, L. M. Articles by Coffer, P. J. Search for Related Content PubMed PubMed Citation Articles by Kuijk, L. M. Articles by Coffer, P. J. Related Collections Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation Loes M. Kuijk1,2, Jeffrey M. Beekman2, Janet Koster3, Hans R. Waterham3, Joost Frenkel1, and Paul J. Coffer2,4 Departments of1 General Pediatrics and 2 Pediatric Immunology, University Medical Centre, Utrecht; 3 Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam; and 4 Molecular Immunology Lab, Department of Immunology, University Medical Centre, Utrecht, The Netherlands 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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