Abstract | OBJECTIVE: METHODS: 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. CONCLUSION: In this model, shortage of isoprenoid end products contributes to increased IL-1beta secretion by MK-deficient PBMCs, whereas excess mevalonate does not.
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Authors | Joost Frenkel, Ger T Rijkers, Saskia H L Mandey, Sandra W M Buurman, Sander M Houten, Ronald J A Wanders, Hans R Waterham, Wietse Kuis |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 46
Issue 10
Pg. 2794-803
(Oct 2002)
ISSN: 0004-3591 [Print] United States |
PMID | 12384940
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies
- CD2 Antigens
- CD28 Antigens
- Diterpenes
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Immunoglobulin D
- Interleukin-1
- Polyisoprenyl Phosphates
- Farnesol
- Lovastatin
- geranylgeraniol
- Phosphotransferases (Alcohol Group Acceptor)
- mevalonate kinase
- Mevalonic Acid
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Topics |
- Antibodies
(pharmacology)
- CD2 Antigens
(immunology)
- CD28 Antigens
(pharmacology)
- Cell Division
(drug effects, immunology)
- Cells, Cultured
- Child
- Diterpenes
(metabolism, pharmacology)
- Familial Mediterranean Fever
(immunology, metabolism)
- Farnesol
(metabolism, pharmacology)
- Female
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
(pharmacology)
- Hypergammaglobulinemia
(immunology, metabolism)
- Immunoglobulin D
- Interleukin-1
(metabolism)
- Lovastatin
(pharmacology)
- Male
- Mevalonic Acid
(metabolism, pharmacology)
- Phosphotransferases (Alcohol Group Acceptor)
(metabolism)
- Polyisoprenyl Phosphates
(metabolism, pharmacology)
- T-Lymphocytes
(cytology, drug effects, metabolism)
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