Abstract
TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases. Malfunction of prenylation of proteins results in upregulation of the inflammatory cascade, leading to increased production of proinflammatory cytokines like interleukin-1β (IL-1β), eventually leading to episodic febrile attacks. In vitro, TAK-475 M-I incubation in a concentration dependent manner increased levels of FPP, GGPP, and FOH in human monocytic THP-1 cells. In subsequent experiments, THP-1 cells or human peripheral blood mononuclear cells (PBMCs) were incubated with simvastatin, which inhibits hydroxymethylglutaryl-coenzyme A reductase and thereby decreases levels of the precursors of MDIs, leading to the depletion of MDIs as expected in MKD patients. Increased levels of GGPP and FPP attenuated lipopolysaccharide (LPS)-induced IL-1β production in THP-1 cells and human PBMCs in statin-treated conditions. The MDIs also significantly reduced the damaged cell ratio in this active MKD-like condition. Moreover, TAK-475 M-I directly inhibited LPS-induced IL-1β production from statin-treated THP-1 cells. These results show anti-inflammatory and cytoprotective effects of MDIs via TAK-475 M-I treatment in statin-treated immune cells, suggesting that possible therapeutic effects of TAK-475 treatment in MKD patients.
Highlights
Mevalonate kinase deficiency (MKD) is a rare periodic fever syndrome with autosomal recessive inheritance that is caused by a mutation in the MVK gene encoding mevalonate kinase (MK) (Esposito et al 2014)
mevalonate-derived isoprenoids (MDIs) play a crucial role in the regulation and production of a range of cytokines, and decreased MDI levels are implicated in increases in pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6, C-reactive protein (CRP), and monocyte chemotactic protein-1 (Kostjukovits et al 2015; Mandey et al 2006; Marcuzzi et al 2013)
TAK‐475 M‐I significantly increased the levels of MDIs in THP‐1 cells Effects of TAK-475 M-I on the level of four MDIs; farnesyl diphosphate (FPP), FOH, GGPP and GGOH in human monocytic THP-1 cells were examined
Summary
Mevalonate kinase deficiency (MKD) is a rare periodic fever syndrome with autosomal recessive inheritance that is caused by a mutation in the MVK gene encoding mevalonate kinase (MK) (Esposito et al 2014). MK converts mevalonic acid to mevalonate-5 phosphate, which is the precursor for the synthesis of a range of MDIs, including FPP, FOH, GGPP, GGOH, ubiquinones, and dicarboxylic acids (DCAs) (van der Burgh et al 2013; Tricarico et al 2014; Hubner et al 1993; Xu et al 2015). MDI levels in MKD patients are reported to be decreased (Hubner et al 1993). MDIs play a crucial role in the regulation and production of a range of cytokines, and decreased MDI levels are implicated in increases in pro-inflammatory mediators, including interleukin-1β (IL-1β), interleukin-6, C-reactive protein (CRP), and monocyte chemotactic protein-1 (Kostjukovits et al 2015; Mandey et al 2006; Marcuzzi et al 2013). An increased production of inflammatory cytokines by peripheral blood mononuclear cells (PBMCs), including monocytes, has been suggested as a central mechanism in the inflammatory phenotype of MKD
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