12.2 Mevalonate kinase deficiency: Impaired isoprenoid synthesis induces IL-1beta production via activation of Rac1

Abstract

Mevalonate kinase deficiency is an autosomal recessive disorder characterized by recurring episodes of fever and inflammation. Peripheral blood mononuclear cells from mevalonate kinase deficiency patients secrete high levels of IL-1β when stimulated with lipopolysaccharide (LPS) due to the presence of hyperactive caspase-1. The molecular mechanism of mevalonate kinase deficiency-induced caspase-1 activation remains unclear. We artificially impaired isoprenoid biosynthesis in the monocytic cells (THP-1) with simvastatin, after which cells were stimulated with LPS. Simvastatin-treated THP-1 cells stimulated with LPS demonstrated enhanced release of IL-1β. LPS enhanced transcription of IL-1β., whereas simvastatin enhanced proteolytic activation of IL-1β. This effect was mediated by phosphatidylinositol 3 kinase (PI3K) and protein kinase B (PKB/c-Akt). In addition, simvastatin-induced IL-1β secretion required the small GTPase Rac1. Simvastatin treatment increased the levels of biologically active GTP-bound Rac1 and inhibition of Rac1 reduced simvastatin-mediated IL-1β secretion. Rac1 functioned upstream of PKB, since Rac1 inhibition abolished the effect of simvastatin on PKB. Simvastatin-mediated activation of the Rac1/PI3K/PKB pathway enhanced IL-1β secretion through activation of caspase-1, since inhibition of both Rac1 and PI3K blocked the release of active caspase-1 subunits. The importance of Rac1 in mevalonate kinase deficiency was confirmed when a specific Rac1 inhibitor was shown to inhibit spontaneous IL-1β release by mononuclear cells from mevalonate kinase deficiency patients. Together, these results demonstrate that Rac1, PI3K and PKB are involved in simvastatin-induced secretion of IL-1β through regulation of caspase-1 activity and that Rac1 is a potential new therapeutic target in mevalonate kinase deficiency.