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Objective To explore the possible upstream signal transduction mechanisms responsible for the decrease of glucocorticoid receptor (GR)α/GRβ in chronic rhinosinusitis (CRS) in vitro. Methods The GRα/GRβ decrease cell model was established by IL-1β-induced human nasal epithelia (HNE) in vitro. Changes in the protein and mRNA expression of GRα, GRβ and the key enzymes in the p38MAPK and NF-κB pathways were measured respectively, before and after being induced with different doses of IL-1β and specific inhibitors of p38MAPK and NF-κB. Analysis of variance (ANOVA) was used to analyze the data. Results With IL-1β-induction, the GRα/GRβ ratio declined in both a time-dependent manner and a concentration-dependent manner in HNE, which demonstrated the successful establishment of a GRα/GRβ decrease model in vitro. After cultured HNE were induced with the same set of IL-1β, the p38MAPK and NF-κB signal pathways were also activated. Either a specific inhibitor (SB203580) of the p38MAPK pathway or a specific inhibitor (PDTC) of the NF-κB pathway increased the GRα/GRβ ratio at the meantime of inhibiting their pathways. The expressions of phospho-NF-κBp50 and phospho-NF-κBp65 were significantly decreased by SB203580. PDTC had no influence on the expression of the key enzymes in the p38MAPK. Conclusion The decrease of GRα/GRβ ratio in HNE induced by IL-1β in vitro is induced through the p38MAPK/NF-κB signal pathways.
RESUMEN
<p><b>OBJECTIVE</b>To explore the upstream signal transduction mechanism responsible for the decrease of the ratio of the two glucocorticoid receptor (GR) subunits (GRα and GRβ) in nasal polyp in vitro.</p><p><b>METHODS</b>The GRα/GRβ decrease cell model was established by lipopolysaccharide (LPS)-induced human nasal epithelia (HNE) of nasal polyp in vitro. Changes in the protein and mRNA expression of GRα, GRβ and the key enzymes in the p38MAPK, ERK and JNK signal pathways were measured, respectively, before and after being induced with different doses of LPS and specific inhibitors of p38MAPK, JNK and ERK. SPSS 16.0 software (Analysis of variance, ANOVA) was used to analyze the data.</p><p><b>RESULTS</b>With the LPS induction, the GRα/GRβ ratio declined in both a time-dependent manner and a concentration-dependent manner in HNE, which demonstrated the successful establishment of a GRα/GRβ decrease model in vitro. After cultured HNE were induced with the same set of LPS, the p38MAPK, ERK and JNK signal pathways were also activated. The mRNA expression of p38MAPK and JNK in each LPS-induced group (17.14 ± 1.50, 22.34 ± 2.78, 30.12 ± 1.07; 2.51 ± 0.13, 3.79 ± 0.67, 4.41 ± 0.83; 25.62 ± 1.77, 31.33 ± 1.97, 37.25 ± 2.46) was significantly higher than that (7.39 ± 0.31, 2.04 ± 0.34, 2.38 ± 0.35) in the control group (χ² value was 15.347, 18.331, 14.671, all P < 0.01). Either a specific inhibitor (SB203580) of the p38MAPK pathway or a specific inhibitor (SP600125) of the JNK pathway increased the GRα/GRβ ratio at the meantime of inhibiting their pathways. SB203580 exhibited a much stronger increase effect on GRα/GRβ ratio than SP600125. The specific inhibitors (PD98059) of ERK had no influence on the expression of GR isoforms.</p><p><b>CONCLUSIONS</b>The above results demonstrated that the decrease of GRα/GRβ ratio in HNE induced by LPS in vitro is mediated through the p38MAPK and JNK signal pathways. It is possible to improve the treatment effect of GC resistance in nasal polyp by targeting these specific signal pathways.</p>