Role of 11 beta-hydroxysteroid dehydrogenase type 1 in the development of atopic dermatitis

Abstract

Glucocorticoids (GCs) are potent anti-inflammatory drugs, the secretion of which is mediated and controlled by the hypothalamic-pituitary-adrenal axis. However, they are also secreted de novo by peripheral tissues for local use. Several tissues express 11 beta -hydroxysteroid dehydrogenase 1 (11 beta -HSD1), including the skin. The inactive GC cortisone is converted by 11 beta -HSD1 to active GC cortisol, which is responsible for delayed wound healing during a systemic excess of GC. However, the role of 11 beta -HSD1 in inflammation is unclear. We assessed whether 11 beta -HSD1 affects the development of atopic dermatitis (AD) in vitro and in vivo. The expression of 11 beta -HSD1 in the epidermis of AD lesions was higher than that in the epidermis of healthy controls. Knockdown of 11 beta -HSD1 in human epidermal keratinocytes increased the production of thymic stromal lymphopoietin. In an oxazolone-induced mouse model of AD, localized inhibition of 11 beta -HSD1 aggravated the development of AD and increased serum cytokine levels associated with AD. Mice with whole-body knockout (KO) of 11 beta -HSD1 developed significantly worse AD upon induction by oxazolone. We propose that 11 beta -HSD1 is a major factor affecting AD pathophysiology via suppression of atopic inflammation due to the modulation of active GC in the skin.