Objective. Mevalonate kinase deficiency (MKD) is an autosomal-recessive disorder characterized by recurring episodes of inflammation. MK catalyzes the phosphorylation of mevalonic acid, which is an early step in isoprenoid biosynthesis. The goal of our study was to determine whether a temporary shortage of certain isoprenoid end products and/or the accumulation of mevalonic acid is the cause of interleukin-1␤ (IL-1␤) secretion in MKD.Methods. We studied the effect of the addition of intermediate metabolites and inhibitors of the isoprenoid biosynthesis pathway on IL-1␤ secretion by peripheral blood mononuclear cells (PBMCs) of patients with MKD and healthy controls.Results. Inhibition of enzymes involved in geranylgeranyl pyrophosphate (GGPP) synthesis or geranylgeranylation of proteins led to a marked increase of lipopolysaccharide-stimulated IL-1␤ secretion in PBMCs of control subjects. Furthermore, the increased IL-1␤ secretion by PBMCs of patients with MKD was reversed by supplementation with GGPP as well as with mevalonic acid. IL-1␤ secretion was increased only when control PBMCs were incubated with excessive amounts of mevalonic acid. Finally, a reduction in IL-1␤ secretion by MKD PBMCs was also observed when sterol biosynthesis was inhibited, favoring nonsterol isoprenoid biosynthesis. Conclusion.Our results indicate that a shortage of geranylgeranylated proteins, rather than an excess of mevalonate, is likely to cause increased IL-1␤ secretion by PBMCs of patients with MKD.

Objective. To investigate whether the increased interleukin-1␤ (IL-1␤) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds.Methods. The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 ؉ CD28.Results. Lovastatin induced a 15-fold rise in IL-1␤ secretion by normal anti-CD2 ؉ CD28-stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1␤ secretion. Stimulated MKdeficient cells secreted 9-fold more IL-1␤ than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1␤ secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1␤ secretion by these cells.Conclusion. In this model, shortage of isoprenoid end products contributes to increased IL-1␤ secretion by MK-deficient PBMCs, whereas excess mevalonate does not.