MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps - 19/04/17
, Anselm Morell, PhD c, d, ∗, Beatriz Ballester, PhD d, Miguel Armengot, MD, PhD e, f, Esteban Morcillo, MD, PhD c, d, g, Julio Cortijo, PhD c, d, hAbstract |
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.
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.
Le texte complet de cet article est disponible en PDF.Key words : MUC4, corticosteroid resistance, nasal polyp, chronic rhinosinusitis, glucocorticoid receptor
Abbreviations used : CRSwNP, CT, Ct, DMEM, EGF, ERK, GAPDH, GR, GRE, hsp, LAR II, MKP1, MUC4, NP, NP-AIA, NP-ATA, NP-CR, NPwA, PGN, siRNA, TLR
Plan
| Supported by grants SAF2014-55322-P (to J.C.), FIS PI14/01733 (to J.M.), FIS PI11/02618 (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. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 3
P. 855 - mars 2017 Retour au numéro
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