Glucocorticoid (GC) excess adversely affects many aspects of skin homeostasis, characteristics of which are also seen during ageing (e.g. poor wound healing). The mechanisms underlying this remain unclear. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates cortisol, independently of circulating concentrations, and we have previously demonstrated increased 11β-HSD1 expression in human dermal fibroblasts (HDF) from aged donors. We have now examined 11β-HSD1 activity and the regulation of GC target genes in paired 3mm skin biopsies from photo-protected (PP) and photo-exposed (PE) sites in cohorts of young and aged humans. Following ethical approval and informed consent, we demonstrated elevated 11β-HSD1 activity in old (>60 years, n=20) vs. young (2030 years, n=20) donors at both PP (42%, P<0.01) and PE (26%, P<0.05) sites. 11β-HSD1 activity was also increased in donor-matched PE vs. PP (photo-aged) tissue in both the young (34%, P<0.001) and old (21%, P<0.05) cohorts. To establish the functional relevance of these findings, we examined mRNA levels of 108 genes regulating skin homeostasis (collagen biosynthesis, structural, signalling and stress responses) in untreated skin biopsies (young/old/PE/PP), HDFs treated with 100 nM cortisol, and biopsies treated with cortisone ± an 11β-HSD1-specific inhibitor. This approach identified 23 genes potentially regulated by 11β-HSD1 in ageing skin. Importantly, dual specificity phosphatase-1 (MAPK p38 inhibitor) was increased in aged PP (2.3-fold, P<0.05) and PE (1.6-fold, P<0.05) biopsies, increased in cortisol-treated HDFs (2.1-fold, P<0.01) and decreased with inhibitor treatment in young PE biopsies (0.66-fold, P<0.05). Decreased p38 signalling impairs macrophage function and increases edema, offering a mechanism for impaired inflammatory and wound healing responses in the elderly. Moreover, we identified a similar aging- and 11β-HSD1-dependant increase in the expression of collagen-degrading matrix metalloproteinases (e.g. MMP-3). Our data shows that increased 11β-HSD1 activity in ageing skin can modify GC target gene expression, contributing to adverse modifications in skin architecture, homeostasis and function.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.