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11beta-hydroxysteroid dehydrogenase type 1 in skin: effects of stress, aging and UV

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Dates:12 May 2014
Times:13:00 - 14:00
What is it:Seminar
Organiser:Faculty of Life Sciences
Who is it for:University staff
Speaker:Ana Tiganescu
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  • In category "Seminar"
  • In group "(FLS) Special Seminars"
  • By Faculty of Life Sciences

Systemic glucocorticoid (GC) excess (i.e. Cushing’s syndrome, stress) shares many features of organismal ageing e.g. impaired brain function, muscle wasting, osteoporosis and hypertension. In skin, shared features including thinning, atrophy, telangiectasia, delayed wound healing (WH) and increased infection risk are further exacerbated by chronic ultraviolet radiation (UV) exposure. The ubiquitously expressed enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regulates peripheral GC availability by activating cortisol from cortisone (or corticosterone from 11-dehydrocorticosterone in rodents) in an NADPH-dependent manner. Previously, we characterized 11beta-HSD1 expression and demonstrated increased activity in skin from aged mice and humans which was exacerbated in skin of UV-exposed origin. Further, 11beta-HSD1 null (KO) mice were protected from age-associated dermal atrophy and displayed accelerated WH. Here, we demonstrate elevated 11beta-HSD1 expression/activity during early mouse skin wound healing, localizing to numerous infiltrating inflammatory cells. In comparison, de novo steroidogenic synthesis of corticosterone from progesterone is negligible due to absence of Cyp11b1 expression (required for 11-deoxycorticosterone conversion to corticosterone). Topical treatment with the 11beta-HSD1 inhibitor carbenoxolone (CBX) does not affect epidermal thickness, barrier disruption/recovery or WH in young SKH1 (hairless) mice. However, CBX normalizes restraint stress-induced WH impairment and improves WH in Cushingoid mice (100µg/ml corticosterone in drinking water) suggesting that adverse features of systemic GC excess are mediated by local 11beta-HSD1 activity. Indeed, CBX also improves epidermal thickness and barrier disruption abnormalities in unwounded Cushingoid mouse skin – supported by in vitro studies demonstrating promotion of keratinocyte differentiation by GC. 11beta-HSD1 activity further increases in wounds from aged mice. Interestingly, WH is unaffected by age and CBX treatment delays WH in aged mice, coupled with increased expression of pro-inflammatory cytokines. Moreover, CBX fails to improve age-associated impairments in barrier function and disruption highlighting the importance of early therapeutic intervention. Finally, we demonstrate direct upregulation of 11beta-HSD1 expression and activity by UVB in a time- and dose-dependent manner in vivo, resulting from UV-induced keratinocyte hyperproliferation. These findings suggest topical 11beta-HSD1 blockade may protect against the deleterious effects of systemic GC excess, particularly when 11beta-HSD1 activity is raised (e.g. elderly patients). 11beta-HSD1 inhibitors could also provide a novel treatment for chronic wounds (e.g. diabetic ulcers) where inflammation-driven local GC activation may be a key underlying factor.

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Ana Tiganescu

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Rachel Abbott

0161 275 5360

rachel.abbott@manchester.ac.uk

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