Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps - 05/02/15
, Teresa Peiró, PhD c, d, ∗, Miquel Armengot, PhD, MD e, f, Soledad Frias, MD e, Anselm Morell c, d, Adela Serrano, PhD c, g, Julio Cortijo, PhD a, c, d, gAbstract |
Background |
A number of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) are resistant to oral corticosteroids. Mucin 1 (MUC1) shows anti-inflammatory properties, and its cytoplasmic tail (CT) interacts with transcription factors, facilitating their nuclear translocation. Because glucocorticoid receptor (GR) nuclear translocation is key to the anti-inflammatory effect of corticosteroids, we hypothesized that MUC1 is involved in the effectiveness of corticosteroids.
Objective |
To analyze the role of MUC1 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.
Methods |
Seventy-three patients with CRSwNP took oral corticosteroids for 15 days. Corticosteroid resistance was evaluated by nasal endoscopy. The expression of MUC1 and MUC1 CT was evaluated by real-time PCR, Western blotting, and immunohistochemistry. Beas-2B knockdown with RNA interference for MUC1 (siRNA-MUC1) was used to analyze the role of MUC1 in the anti-inflammatory effects of dexamethasone.
Results |
Nineteen patients had nasal polyps that were resistant to oral corticosteroids (NP-CR). MUC1 expression was downregulated in these patients. Primary epithelial cells from patients with NP-CR were insensitive to the anti-inflammatory effects of dexamethasone. In siRNA-MUC1 Beas-2B, dexamethasone showed weaker anti-inflammatory effects, a reduced inhibition of phospho-extracellular-signal-regulated kinases 1/2, a less severe mitogen-activated protein kinase phosphatase 1 increase, and a reduced GR nuclear translocation. Immunoprecipitation experiments revealed that MUC1-CT and GRα form protein complexes and translocate to the nucleus in response to dexamethasone. MUC1-CT–GRα complex was downregulated in NP-CR tissue.
Conclusion |
MUC1-CT participates in the corticosteroid response that mediates GRα nuclear translocation. The low expression of MUC1 in patients with CRSwNP may participate in corticosteroid resistance.
Le texte complet de cet article est disponible en PDF.Key words : MUC1, corticosteroid resistance, nasal polyp, chronic rhinosinusitis, glucocorticoid receptor
Abbreviations used : CRSwNP, CT, ERK1/2, GR, hsp, MKP1, MIF, NP, NP-AIA, NP-ATA, NP-CR, NPwA, PGN, TLR
Plan
| This work was supported by grants SAF2011-26443 (Spanish government; to J.C.), FIS CP11/00293 (Spanish government; to J.M.), CIBERES (Spanish government; CB06/06/0027), ADE10/00020 (Spanish government), FIS PI11/02618 (M.A.), and ACIF/2010/114 (Generalitat Valenciana; to T.P.) as well as research grants from Regional Government Prometeo II/2013/014 (J.C., J.M.) “Generalitat Valenciana.” Support from the CENIT program (Spanish government) was obtained. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 135 - N° 2
P. 470-476 - février 2015 Retour au numéro
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