Abstract
Elevated level of active glucocorticoid (GC) deteriorates skin barrier function. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent enzyme converting inactive GC to active GC. Elevated active GC due to increased 11β-HSD1 expression might contribute to barrier impairment in aged skin and diabetic skin. We believe that the increase of 11β-HSD1 expression is a main cause of barrier abnormalities in diabetic skin and perform this study to elucidate the effect of a new 11β-HSD1 inhibitor. We compared it with a proven inhibitor in the cultured keratinocytes inducing typically 11β-HSD1 activation with dexamethasone treatment, UVB irradiation, and high glucose treatment, and the db/db mice as a type 2 diabetes murine model. In the cultured medium, cortisol, 11β-HSD1, and cytokines were measured. Also, in the db/db mice with a two-week application of 11β-HSD1 inhibitors, skin barrier function, HbA1c, corticosterone, 11β-HSD1, and cytokines were measured. In cultured keratinocytes, all concentrations and mRNA levels of cortisol, 11β-HSD1, and cytokines were decreased by both 11β-HSD1 inhibitors. In the db/db mice, both inhibitors improved skin barrier function and reduced serum level of HbA1c and skin expression of corticosterone, 11β-HSD1, and cytokines. A new 11β-HSD1 inhibitor, “11b-0048”, showed a significant inhibitory effect on the expression of 11β-HSD1 in keratinocytes activated by various conditions and diabetic skin.