Document Detail

A role for geranylgeranylation in interleukin-1beta secretion.
MedLine Citation:
PMID:  17075828     Owner:  NLM     Status:  MEDLINE    
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. CONCLUSION: 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.
Saskia H L Mandey; Loes M Kuijk; Joost Frenkel; Hans R Waterham
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  54     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-12-04     Completed Date:  2006-12-29     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3690-5     Citation Subset:  AIM; IM    
Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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MeSH Terms
Anti-Inflammatory Agents / pharmacology
Bodily Secretions / drug effects
Diphosphonates / pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
Inflammation / immunology,  metabolism*
Interleukin-1beta / metabolism*,  secretion*
Leukocytes, Mononuclear / immunology,  metabolism,  secretion
Mevalonic Acid / metabolism
Phosphotransferases (Alcohol Group Acceptor) / deficiency*
Protein Prenylation / immunology*
Simvastatin / pharmacology
Terpenes / metabolism
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Diphosphonates; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Interleukin-1beta; 0/Terpenes; 150-97-0/Mevalonic Acid; 40391-99-9/pamidronate; 79902-63-9/Simvastatin; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC kinase

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