Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 602, Issue 2-3, Pages 432-438Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2008.11.040
Keywords
Mast cell; Statin; Fluvastatin; Degranulation; Geranylgeranylation; Cytosolic Ca2+
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [20228005] Funding Source: KAKEN
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We evaluated the pharmacological effect of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) on mast cell degranulation in RBL-2H3 cells. A hydrophilic statin (pravastatin) did not inhibit degranulation induced by dinitrophenol-human serum albumin (DNP-HSA); in contrast, lipophilic statins (simvastatin, fluvastatin and atorvastatin) inhibited DNP-HSA-induced degranulation in that order. The inhibitory effects were completely attenuated by simultaneous treatment with 100-1000 mu M mevalonic acid for 4 h. We used fluvastatin to clarify the mechanism of the statin-mediated inhibitory action of mast cell degranulation. Fluvastatin (3 mu M) had no effect on Ca2+ release from the endoplasmic reticulum or Ca2+ influx in the DNP-HSA- or thapsigargin-stimulated cells. Fluvastatin treatment also had no effect on the total granule content of the cell or sensitivity to DNP-HSA and IgE. Fluvastatin (3 mu M, 24 h treatment) also failed to affect the morphology, proliferation, and viability of RBL-2H3 cells. Geranylgeranyl transferase inhibitor, GGTI-286 (20 mu M), but not farnesyl transferase inhibitor, FPTIII (20 mu M), inhibited the DNP-HSA-induced degranulation. The GGTI-286-induced inhibitory action was not associated with a decrease in the cytoplasmic Ca2+ level. In conclusion, fluvastatin at a lower concentration range inhibited DNP-HSA-induced degranulation without affecting the cytoplasmic Ca2+ response and also without changing the amount of granule content and proliferation of the mast cells. The statin-induced inhibitory action may be mediated by the suppression of geranylgeranyl transferase via the depletion of intracellular mevalonic acid. (C) 2008 Elsevier B.V. All rights reserved.
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