| Background: Steroid-resistant asthma seriously affects patients' quality of life and increases their financial burden.Finding effective treatments is an urgent problem to be solved.One of the mechanisms of glucocorticoid resistance in asthma is necroptosis of airway epithelial cells caused by over-activated inflammatory factors.Mucin 1(MUC1),which is widely expressed in airway epithelial cells,has an inhibitory effect on inflammation and cell death.Studies have shown that MUC1 deficiency significantly inhibits the anti-inflammatory effects of dexamethasone(Dex)in severe asthma.However,the role of MUC1 on Dex-mediated anti-necroptosis has still not been studied.Objective: To investigate whether MUC1 downregulation attenuates the anti-necroptosis effect of Dex on airway epithelial cells and explain its underlying mechanism.Methods: MUC1 small interfering RNA(si RNA)was transfected into human bronchial epithelial cells(16HBE),and then stimulated with tumor necrosis factor(TNF-?)and Dex.Flow cytometry was used to analyze the necroptosis of cells.Immunoblotting was used to detect the expressions of MUC1,glucocorticoid receptor(GR)?,GR?,nuclear factor-?B(NF-?B p65),p-p65 and histone deacetylase-2(HDAC2).In addition,nuclear translocation of MUC1 and GR? was examined by immunofluorescence.Results: TNF-? induced necroptosis in 16 HBE cells,which was promoted by MUC1 downregulation.However,dexamethasone failed to inhibit TNF-?-induced necroptosis in 16 HBE cells with MUC1 downregulation.In addition,we found that MUC1 downregulation inhibits GR? nuclear translocation and attenuates the inhibitory effect of Dex on p-p65.Conclusion: MUC1 downregulation promoted TNF-?-induced 16 HBE necroptosis,and which could not be inhibited by dexamethasone.In addition,MUC1 participates glucocorticoid resistance in TNF-?-induced necroptosis by inhibiting GR? nuclear translocation and attenuating the inhibitory effect of Dex on p-p65. |
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