Differential expression of 11 beta-hydroxysteroid dehydrogenase type 1 and 2 in mild and moderate/severe persistent allergic nasal mucosa and regulation of their expression by Th2 cytokines

Abstract

BackgroundGlucocorticoids are used to treat allergic rhinitis, but the mechanisms by which they induce disease remission are unclear. 11-hydroxysteroid dehydrogenase (11-HSD) is a tissue-specific regulator of glucocorticoid responses, inducing the interconversion of inactive and active glucocorticoids. ObjectiveWe analysed the expression and distribution patterns of 11-HSD1, 11-HSD2, and steroidogenic enzymes in normal and allergic nasal mucosa, and cytokine-driven regulation of their expression. The production levels of cortisol in normal, allergic nasal mucosa and in cultured epithelial cells stimulated with cytokines were also determined. MethodsThe expression levels of 11-HSD1, 11-HSD2, steroidogenic enzymes (CYP11B1, CYP11A1), and cortisol in normal, mild, and moderate/severe persistent allergic nasal mucosa were assessed by real-time PCR, Western blot, immunohistochemistry, and ELISA. The expression levels of 11-HSD1, 11-HSD2, CYP11B1, CYP11A1, and cortisol were also determined in cultured nasal epithelial cell treated with IL-4, IL-5, IL-13, IL-17A, and IFN-. Conversion ratio of cortisone to cortisol was evaluated using siRNA technique, 11-HSD1 inhibitor, and the measurement of 11-HSD1 activity. ResultsThe expression levels of 11-HSD1, CYP11B1, and cortisol were up-regulated in mild and moderate/severe persistent allergic nasal mucosa. By contrast, 11-HSD2 expression was decreased in allergic nasal mucosa. In cultured epithelial cells treated with IL-4, IL-5, IL-13, and IL-17A, 11-HSD1 expression and activity increased in parallel with the expression levels of CYP11B1 and cortisol, but the production of 11-HSD2 decreased. CYP11A1 expression level was not changed in allergic nasal mucosa or in response to stimulation with cytokines. SiRNA technique or the measurement of 11-HSD1 activity showed that nasal epithelium activates cortisone to cortisol in a 11-HSD-dependent manner. Conclusions and Clinical RelevanceThese results indicate that the localized anti-inflammatory effects of glucocorticoids are regulated by inflammatory cytokines, which can modulate the expression of 11-HSD1, 11-HSD2, and CYP11B1, and by the intracellular concentrations of bioactive glucocorticoids.