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 FcRI 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.
|Number of pages||10|
|Journal||Journal of Immunology|
|State||Published - Feb 15 2016|
Bibliographical noteFunding Information:
We thank Dr. Daniel Conrad for many helpful conversations concerning this manuscript. This work was supported by the National Institutes of Health (Grants 1R01AI101153 and 2R01AI059638 to J.J.R.; Grant 1R01 AI095494 to C.A.O.; Grants HL125353 and CA154314 to C.E.C.; and Grant NH1C06-RR17393 to Virginia Commonwealth University for renovation) and by the Veteran’s Administration (VA Merit Review I BX001792 and Research Career Scientist Award 1 3F-RCS-002 to C.E.C.). Services (VCU Lipidomics/Metabolomics Core Facility) and products in support of the research project were generated in part by the VCU Massey Cancer Center (shared and supported) with funding from National Institutes of Health-National Cancer Institute Cancer Center Support Grant P30 CA016059.
Copyright © 2016 by The American Association of Immunologists, Inc.
ASJC Scopus subject areas
- Immunology and Allergy