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dc.contributor.authorMilara, Javier
dc.contributor.authorMorell, Anselm
dc.contributor.authorBallester, Beatriz
dc.contributor.authorArmengot, Miguel
dc.contributor.authorMorcillo, Esteban
dc.contributor.authorCortijo, Julio
dc.date.accessioned2016-12-05T08:54:05Z
dc.date.available2016-12-05T08:54:05Z
dc.date.issued2016
dc.identifier.citationMILARA, Javier, et al. MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps. Journal of Allergy and Clinical Immunology, 2016ca_CA
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.urihttp://hdl.handle.net/10234/164903
dc.description.abstractBackground 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. Conclusion 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.ca_CA
dc.description.sponsorShipSupported by grants SAF2014-55322-P (to J.C.), FISPI14/01733 (to J.M.), FISPI11/02618 (to M.A.), SAF2015-65368-R (to E.M.), CIBERES (CB06/06/0027), TRACE (TRA2009-0311; Spanish Government), and research grants from Regional Government Prometeo II/2013/014 (to J.C., E.M., and J.M.) Generalitat Valenciana.ca_CA
dc.format.extent21 p.ca_CA
dc.format.mimetypeapplication/pdfca_CA
dc.language.isoengca_CA
dc.publisherElsevierca_CA
dc.relation.isPartOfJournal of Allergy and Clinical Immunology, 2016ca_CA
dc.rightsCopyright © Elsevier B.V.ca_CA
dc.subjectMUC4ca_CA
dc.subjectcorticosteroid resistanceca_CA
dc.subjectnasal polypca_CA
dc.subjectchronic rhinosinusitisca_CA
dc.subjectglucocorticoid receptorca_CA
dc.titleMUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polypsca_CA
dc.typeinfo:eu-repo/semantics/articleca_CA
dc.identifier.doihttp://dx.doi.org/10.1016/j.jaci.2016.06.064
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_CA
dc.relation.publisherVersionhttp://www.sciencedirect.com/science/article/pii/S0091674916309575ca_CA


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