title: Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated respiratory disease.
abstract: BACKGROUND
  We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked.
  
  
  OBJECTIVE
  We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD.
  
  
  METHODS
  Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE2 production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE2, and specific EP receptor agonists.
  
  
  RESULTS
  Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1β-induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE2 or selective EP2 agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP2 receptor expression was normalized by transfection of NP-AERD fibroblasts.
  
  
  CONCLUSIONS
  Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE2 production. This impairment in the generation of PGE2 subsequently reduces its ability to induce IL-1RI.
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: lsmachad@clinic.ub.es.
authors.forename: Liliana
authors.initials: L
authors.lastname: Machado-Carvalho
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Biochemistry Unit, School of Medicine, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Martín
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Pharmacology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Torres
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gabasa
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic, Barcelona, Spain.
authors.forename: Isam
authors.initials: I
authors.lastname: Alobid
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Mullol
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Pujols
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Roca-Ferrer
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Pneumology and Respiratory Allergy Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: Picado
mesh_terms: D000328:Adult; D000368:Aged; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D055963:Asthma, Aspirin-Induced / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000166:cytology; D009298:Nasal Polyps / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone; D001241:Aspirin
keywords: Aspirin-exacerbated respiratory disease; COX-2; E-prostanoid 2 receptor; IL-1 receptor type I; IL-1β; fibroblasts; microsomal prostaglandin E synthase 1; nasal mucosa; nasal polyps; prostaglandin E(2)