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 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), including the skin. The inactive GC cortisone is converted by 11β-HSD1 to active GC cortisol, which is responsible for delayed wound healing during a systemic excess of GC. However, the role of 11β-HSD1 in inflammation is unclear. We assessed whether 11β-HSD1 affects the development of atopic dermatitis (AD) in vitro and in vivo. The expression of 11β-HSD1 in the epidermis of AD lesions was higher than that in the epidermis of healthy controls. Knockdown of 11β-HSD1 in human epidermal keratinocytes increased the production of thymic stromal lymphopoietin. In an oxazolone-induced mouse model of AD, localized inhibition of 11β-HSD1 aggravated the development of AD and increased serum cytokine levels associated with AD. Mice with whole-body knockout (KO) of 11β-HSD1 developed significantly worse AD upon induction by oxazolone. We propose that 11β-HSD1 is a major factor affecting AD pathophysiology via suppression of atopic inflammation due to the modulation of active GC in the skin.
Highlights
Glucocorticoids (GCs) are potent anti-inflammatory drugs, the secretion of which is mediated and controlled by the hypothalamic–pituitary–adrenal axis
6 and 24 h of polycytidylic acid (poly I):C and IL-4 treatment, the mRNA expression level of 11β-HSD1 tended to decrease in small interfering RNA (siRNA)-transfected normal human epidermal keratinocytes (NHEK) (Fig. 1a)
11β-HSD1 siRNA transfection knocked down 11β-HSD1 expression and 11β-HSD1 was responsible for the regulation of cortisol production
Summary
Glucocorticoids (GCs) are potent anti-inflammatory drugs, the secretion of which is mediated and controlled by the hypothalamic–pituitary–adrenal axis They are secreted de novo by peripheral tissues for local use. To hapten-induced dermatitis was exacerbated and the response to topical 11-dehydrocorticosterone was attenuated in keratinocyte-specific 11β-HSD1 (HSD11b1) knockout (KO) mice compared with the reactions in WT mice. These findings confirmed that GCs exert their immunosuppressive effect through 11β-HSD124. 11β-HSD1 is involved in the cutaneous side effects caused by excess GCs and plays a key role in local anti-inflammatory activity in keratinocytes
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