Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.
OBJECTIVE
To investigate whether the increased interleukin-1beta (IL-1beta) 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-1beta 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-1beta secretion. Stimulated MK-deficient cells secreted 9-fold more IL-1beta than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1beta 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-1beta secretion by these cells.


CONCLUSIONS
In this model, shortage of isoprenoid end products contributes to increased IL-1beta secretion by MK-deficient PBMCs, whereas excess mevalonate does not.
Frenkel
Joost
J
Division of Pediatrics, Wilhelmina Children's Hospital, KE.04.133.1, University Medical Center Utrecht, PO Box 85090, 3580 AB Utrecht, The Netherlands. j.frenkel@wkz.azu.nl
Rijkers
Ger T
GT
Mandey
Saskia H L
SH
Buurman
Sandra W M
SW
Houten
Sander M
SM
Wanders
Ronald J A
RJ
Waterham
Hans R
HR
Kuis
Wietse
W
D000906:Antibodies / Q000494:pharmacology; D018801:CD2 Antigens / Q000276:immunology; D018106:CD28 Antigens / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology; D010505:Familial Mediterranean Fever / Q000276:immunology / Q000378:metabolism*; D005204:Farnesol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006942:Hypergammaglobulinemia / Q000276:immunology / Q000378:metabolism*; D007072:Immunoglobulin D; D007375:Interleukin-1 / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000906:Antibodies; D018801:CD2 Antigens; D018106:CD28 Antigens; D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007072:Immunoglobulin D; D007375:Interleukin-1; D011106:Polyisoprenyl Phosphates; D005204:Farnesol; D008148:Lovastatin; C017338:geranylgeraniol; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D008798:Mevalonic Acid