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

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2016 Jan 17

PMID 26773154

Citations 18

Authors

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

Affiliations

Soon will be listed here.

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 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.

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