Javier Milara1, Teresa Peiró2, Miquel Armengot3, Soledad Frias4, Anselm Morell2, Adela Serrano5, Julio Cortijo6. 1. Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; Department of Biotechnology, Universidad Politécnica de Valencia, Valencia, Spain; Research Foundation of General Hospital of Valencia, Valencia, Spain. Electronic address: xmilara@hotmail.com. 2. Research Foundation of General Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain. 3. Rhinology Unit, University General Hospital Consortium, Valencia, Spain; Department of Medicine, Faculty of Medicine, University of Valencia, Valencia, Spain. 4. Rhinology Unit, University General Hospital Consortium, Valencia, Spain. 5. Research Foundation of General Hospital of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain. 6. Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; Research Foundation of General Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain.
Abstract
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.
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.
Authors: Robert J Taylor; Rodney J Schlosser; Zachary M Soler; Jose L Mattos; Jennifer K Mulligan Journal: Int Forum Allergy Rhinol Date: 2018-05-02 Impact factor: 3.858