title: Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease.
abstract: Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 μM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.
authors.affiliation: Departments of 1 Medicine and.|2 Division of Rheumatology, Immunology, and Allergy.
authors.forename: Katherine N
authors.identifier: http://orcid.org/0000-0002-8549-1835
authors.initials: KN
authors.lastname: Cahill
authors.affiliation: Departments of 1 Medicine and.|3 Channing Division of Network Medicine, and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.affiliation: Departments of 1 Medicine and.|3 Channing Division of Network Medicine, and.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 3 Channing Division of Network Medicine, and.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: 3 Channing Division of Network Medicine, and.
authors.forename: Derek
authors.initials: D
authors.lastname: Thibault
authors.affiliation: 4 Harvard School of Public Health, Boston, Massachusetts; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Baccarelli
authors.affiliation: 4 Harvard School of Public Health, Boston, Massachusetts; and.
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.affiliation: 5 Surgery, Harvard Medical School, Boston, Massachusetts.|6 Department of Otology and Laryngology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Neil
authors.initials: N
authors.lastname: Bhattacharyya
authors.affiliation: 7 Asthma and Allergic Disease Center, Carter Immunology Center, University of Virginia Health System, Charlottesville, Virginia.
authors.forename: John W
authors.initials: JW
authors.lastname: Steinke
authors.affiliation: Departments of 1 Medicine and.|2 Division of Rheumatology, Immunology, and Allergy.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Boyce
authors.affiliation: Departments of 1 Medicine and.|2 Division of Rheumatology, Immunology, and Allergy.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Laidlaw
mesh_terms: D000107:Acetylation; D000328:Adult; D055963:Asthma, Aspirin-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001900:Boston; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009298:Nasal Polyps / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014768:Virginia
chemical_list: C544312:11,15-O-dimethylprostaglandin E2; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C545644:PTGER2 protein, human; D012333:RNA, Messenger; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015232:Dinoprostone
keywords: DNA methylation; E prostanoid type 2 receptor; aspirin-exacerbated respiratory disease; histone acetylation; prostaglandin E2