A role for geranylgeranylation in interleukin-1beta secretion.
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-1beta (IL-1beta) secretion in MKD.


METHODS
We studied the effect of the addition of intermediate metabolites and inhibitors of the isoprenoid biosynthesis pathway on IL-1beta 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-1beta secretion in PBMCs of control subjects. Furthermore, the increased IL-1beta secretion by PBMCs of patients with MKD was reversed by supplementation with GGPP as well as with mevalonic acid. IL-1beta secretion was increased only when control PBMCs were incubated with excessive amounts of mevalonic acid. Finally, a reduction in IL-1beta secretion by MKD PBMCs was also observed when sterol biosynthesis was inhibited, favoring nonsterol isoprenoid biosynthesis.


CONCLUSIONS
Our results indicate that a shortage of geranylgeranylated proteins, rather than an excess of mevalonate, is likely to cause increased IL-1beta secretion by PBMCs of patients with MKD.
Mandey
Saskia H L
SH
Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Kuijk
Loes M
LM
Frenkel
Joost
J
Waterham
Hans R
HR
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D012634:Bodily Secretions / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D000077268:Pamidronate; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D017368:Protein Prenylation / Q000276:immunology*; D019821:Simvastatin / Q000494:pharmacology; D013729:Terpenes / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D013729:Terpenes; D019821:Simvastatin; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D000077268:Pamidronate; D008798:Mevalonic Acid