title: Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects.
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.
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Elizabeth Motunrayo
authors.initials: EM
authors.lastname: Kolawole
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Jamie Josephine Avila
authors.initials: JJ
authors.lastname: McLeod
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Victor
authors.identifier: http://orcid.org/0000-0002-4594-5994
authors.initials: V
authors.lastname: Ndaw
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-6837-3028
authors.initials: D
authors.lastname: Abebayehu
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Brian O
authors.initials: BO
authors.lastname: Barnstein
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Travis
authors.initials: T
authors.lastname: Faber
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Spence
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Marcela
authors.initials: M
authors.lastname: Taruselli
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Anuya
authors.initials: A
authors.lastname: Paranjape
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Haque
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Amina A
authors.initials: AA
authors.lastname: Qayum
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: Qasim A
authors.initials: QA
authors.lastname: Kazmi
authors.affiliation: Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298;
authors.forename: Dayanjan S
authors.identifier: http://orcid.org/0000-0002-2124-5109
authors.initials: DS
authors.lastname: Wijesinghe
authors.affiliation: Department of Family and Community Health, Virginia Commonwealth University School of Nursing, Richmond, VA 23298;
authors.forename: Jamie L
authors.identifier: http://orcid.org/0000-0001-8856-3227
authors.initials: JL
authors.lastname: Sturgill
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298; Research and Development, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; Virginia Commonwealth University Institute of Molecular Medicine, Richmond, VA 23298; and.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors.forename: David B
authors.identifier: http://orcid.org/0000-0003-1989-8255
authors.initials: DB
authors.lastname: Straus
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208.
authors.forename: Carole A
authors.identifier: http://orcid.org/0000-0003-1380-9186
authors.initials: CA
authors.lastname: Oskeritzian
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284; jjryan@vcu.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D001491:Basophils / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D051231:Farnesyltranstransferase / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000276:immunology; D007211:Indoles / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000214:Acyl Coenzyme A; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D007073:Immunoglobulin E; D000077340:Fluvastatin; D051231:Farnesyltranstransferase; D008798:Mevalonic Acid