Abstract
BackgroundTo explore the upstream signal transduction mechanisms responsible for the imbalanced expression of glucocorticoid receptor (GR) isoforms in chronic rhinosinusitis (CRS) mucosa.MethodsAn in vitro model of Glucocorticoid resistance was established by inducing nasal polyp tissue with IL-1β. Changes in the protein and mRNA expression of GRα, GRβ and the key enzymes in the p38 MAPK and JNK signal pathways were measured, respectively, before and after being induced with different doses of IL-1β and specific inhibitors of p38 MAPK, JNK, ERK, PI3K and PKC. The Glucocorticoid sensitivity was measured using in vitro Glucocorticoid binding assay. Analysis of variance (ANOVA) was used to analyze the data.ResultsThe mRNA and protein expression levels of GRα, GRβ and key enzymes of the p38 MAPK and JNK pathways increased both in time- and concentration-dependent manners in IL-1β-induced nasal polyp tissue. The expression of GRβ increased more significantly than that of GRα, and the GRα/GRβ ratio decreased in time- and concentration-dependent manners. Statistically significant differences were found in the GRα/GRβ ratio and the mRNA expression of phospho-p38 MAPK and phospho-JNK between the IL-1β-induced groups and the control groups (P < 0.05). Either a specific inhibitor of the p38 MAPK pathway or a specific inhibitor of the JNK pathway increased the GRα/GRβ ratio and the Glucocorticoid affinity. None of the specific inhibitors of ERK, PI3K or PKC had any influence on the expression of GR isoforms.ConclusionOur results demonstrated that the imbalanced expression of GR isoforms in nasal polyp tissue induced by IL-1β in vitro is mediated through the p38 MAPK and JNK signal pathways.
Highlights
To explore the upstream signal transduction mechanisms responsible for the imbalanced expression of glucocorticoid receptor (GR) isoforms in chronic rhinosinusitis (CRS) mucosa
Establishment of a GC resistance model of nasal polyps induced by Interleukin-1 beta (IL-1β) in vitro IL-1β induced a decrease in the GRα/GRβ ratio in a dosedependent manner in cultured nasal polyps in vitro
The mRNA and protein expression of GRα and GRβ in the IL-1β-induced nasal polyp tissues increased in a concentration-dependent manner, and the expression of GRβ increased more significantly than that of GRα (Figure 1A,B and C)
Summary
To explore the upstream signal transduction mechanisms responsible for the imbalanced expression of glucocorticoid receptor (GR) isoforms in chronic rhinosinusitis (CRS) mucosa. Glucocorticoid (GC) therapy is widely used to control mucosal inflammation in CRS cases and to slow the growth of nasal polyps [3,4,5]. There are two human GR isoforms (GRα and GRβ), and GC’s physiological actions are mainly mediated by GRα, which is far more abundant than GRβ in nasal mucosa [6,7]. GRβ negatively regulates GRα by forming GRα/ GRβ heterodimers, reducing the anti-inflammatory effect of GC [8,9]. Recent studies have clearly demonstrated that a higher expression of GRβ led to a lower GRα/GRβ ratio in the nasal polyps of GC-resistant CRS cases than
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
