title: MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps.
abstract: BACKGROUND
  Current evidence suggests that membrane-tethered mucins could mediate corticosteroid efficacy, interacting with glucocorticoid receptor (GR) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucin 4 (MUC4)-tethered mucin is expressed in nasal polyp (NP) epithelial cells and upregulated under inflammatory conditions. Moreover, MUC4β has the capacity to interact with other intracellular proteins. We hypothesized that MUC4 modulates corticosteroid efficacy of patients with CRSwNP.
  
  
  OBJECTIVE
  We sought to analyze the role of MUC4 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.
  
  
  METHODS
  Eighty-one patients with CRSwNP took oral corticosteroids for 15 days. Corticosteroid resistance was evaluated by using nasal endoscopy. Expression of MUC4 and MUC4β was evaluated by means of real-time PCR, Western blotting, and immunohistochemistry. BEAS-2B knockdown with RNA interference for MUC4 (small interfering RNA [siRNA]-MUC4) was used to analyze the role of MUC4 in the anti-inflammatory effects of dexamethasone.
  
  
  RESULTS
  Twenty-two patients had NPs resistant to oral corticosteroids. MUC4 expression was upregulated in these patients. In siRNA-MUC4 BEAS-2B airway epithelial cells dexamethasone produced higher anti-inflammatory effects, increased inhibition of phospho-extracellular signal-regulated kinase 1/2, increased mitogen-activated protein kinase phosphatase 1 expression, and increased glucocorticoid response element activation. Immunoprecipitation and immunofluorescence experiments revealed that MUC4β forms a complex with GRα in the nuclei of NP epithelial cells from corticosteroid-resistant patients.
  
  
  CONCLUSIONS
  MUC4β participates in the corticosteroid resistance process, inhibiting normal GRα nuclear function. The high expression of MUC4 in patients with CRSwNP might participate in corticosteroid resistance.
authors.affiliation: Department of Pharmacy, University Hospital Consortium, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, Jaume I University, Castellon, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain. Electronic address: xmilara@hotmail.com.
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain.
authors.forename: Anselm
authors.initials: A
authors.lastname: Morell
authors.affiliation: CIBERES, Health Institute Carlos III, Valencia, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ballester
authors.affiliation: Rhinology Unit, University Hospital Consortium, Valencia, Spain; Department of Medicine, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Armengot
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain; Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain; Research and Teaching Unit, University Hospital Consortium, Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D002908:Chronic Disease; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D055264:Mucin-4 / Q000235:genetics / Q000276:immunology*; D009298:Nasal Polyps / Q000188:drug therapy*; D011282:Pregnenediones / Q000627:therapeutic use*; D012220:Rhinitis / Q000188:drug therapy*; D012852:Sinusitis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; C524658:MUC4 protein, human; D055264:Mucin-4; D011282:Pregnenediones; D003907:Dexamethasone; C021988:deflazacort
keywords: MUC4; chronic rhinosinusitis; corticosteroid resistance; glucocorticoid receptor; nasal polyp