Fluvastatin suppresses mast cell and basophil IgE responses: Genotype-dependent effects

Elizabeth Motunrayo Kolawole, Jamie Josephine Avila McLeod, Victor Ndaw, Daniel Abebayehu, Brian O. Barnstein, Travis Faber, Andrew J. Spence, Marcela Taruselli, Anuya Paranjape, Tamara T. Haque, Amina A. Qayum, Qasim A. Kazmi, Dayanjan S. Wijesinghe, Jamie L. Sturgill, Charles E. Chalfant, David B. Straus, Carole A. Oskeritzian, John J. Ryan

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1461-1470
Number of pages10
JournalJournal of Immunology
Volume196
Issue number4
DOIs
StatePublished - Feb 15 2016

Bibliographical note

Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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