Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects

Mast cell (MC)- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite standard-of-care therapy. Statins, used to lower serum cholesterol, have immune-modulating activities. We tested the in vitro and in vivo effect...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-02, Vol.196 (4), p.1461-1470
Main Authors: Kolawole, Elizabeth Motunrayo, McLeod, Jamie Josephine Avila, Ndaw, Victor, Abebayehu, Daniel, Barnstein, Brian O, Faber, Travis, Spence, Andrew J, Taruselli, Marcela, Paranjape, Anuya, Haque, Tamara T, Qayum, Amina A, Kazmi, Qasim A, Wijesinghe, Dayanjan S, Sturgill, Jamie L, Chalfant, Charles E, Straus, David B, Oskeritzian, Carole A, Ryan, John J
Format: Article
Language:English
Subjects:
Acyl Coenzyme A - genetics
Acyl Coenzyme A - immunology
Animals
Apoptosis
Basophils - drug effects
Basophils - immunology
Cells, Cultured
Cytokines - biosynthesis
Farnesyltranstransferase - metabolism
Fatty Acids, Monounsaturated - pharmacology
Female
Genotype
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Immunoglobulin E - biosynthesis
Immunoglobulin E - immunology
Indoles - pharmacology
Mast Cells - drug effects
Mast Cells - immunology
Mevalonic Acid - pharmacology
Mice
Mice, Inbred C57BL
Signal Transduction - drug effects
Th2 Cells - immunology
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Summary:Mast cell (MC)- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite standard-of-care therapy. Statins, used to lower serum cholesterol, have immune-modulating activities. We tested the in vitro and in vivo effects of statins on IgE-mediated MC and basophil activation. Fluvastatin showed the most significant inhibitory effects of the six statins tested, suppressing IgE-induced cytokine secretion among mouse MCs and basophils. The effects of fluvastatin were reversed by mevalonic acid or geranylgeranyl pyrophosphatase, and mimicked by geranylgeranyl transferase inhibition. Fluvastatin selectively suppressed key FcεRI signaling pathways, including Akt and ERK. Although MCs and basophils from the C57BL/6J mouse strain were responsive to fluvastatin, those from 129/SvImJ mice were completely resistant. Resistance correlated with fluvastatin-induced upregulation of the statin target HMG-CoA reductase. Human MC cultures from eight donors showed a wide range of fluvastatin responsiveness. These data demonstrate that fluvastatin is a potent suppressor of IgE-mediated MC activation, acting at least partly via blockade of geranyl lipid production downstream of HMG-CoA reductase. Importantly, consideration of statin use for treating MC-associated disease needs to incorporate genetic background effects, which can yield drug resistance.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1501932