TY - JOUR
T1 - Fluvastatin suppresses mast cell and basophil IgE responses
T2 - Genotype-dependent effects
AU - Kolawole, Elizabeth Motunrayo
AU - McLeod, Jamie Josephine Avila
AU - Ndaw, Victor
AU - Abebayehu, Daniel
AU - Barnstein, Brian O.
AU - Faber, Travis
AU - Spence, Andrew J.
AU - Taruselli, Marcela
AU - Paranjape, Anuya
AU - Haque, Tamara T.
AU - Qayum, Amina A.
AU - Kazmi, Qasim A.
AU - Wijesinghe, Dayanjan S.
AU - Sturgill, Jamie L.
AU - Chalfant, Charles E.
AU - Straus, David B.
AU - Oskeritzian, Carole A.
AU - Ryan, John J.
N1 - Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1501932
DO - 10.4049/jimmunol.1501932
M3 - Article
C2 - 26773154
AN - SCOPUS:84958568998
SN - 0022-1767
VL - 196
SP - 1461
EP - 1470
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -