Glucocorticoids (GC) drive multiple adverse effects in skin e.g. epidermal thinning, dermal atrophy and impaired wound healing (WH). Our previous findings indicate increased expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in primary human dermal fibroblasts (HDF), full-thickness skin from older donors and during the inflammatory phase of mouse skin WH. We also reported protection from age-induced dermal atrophy and improved WH in aged 11β-HSD1 KO mice but regulation of GC target genes by 11β-HSD1 in human skin remains unexplored. HDF treated with 10 ng/ml IL-1β induced 11β-HSD1 mRNA by 112-fold (P<0.05, n=3) and activity fourfold (P<0.05, n=4) vs vehicle-treated controls. IL-1β-induced activity was blocked by a selective 11β-HSD1 inhibitor (P<0.05, n=4). Using RNA-seq, we identified 289 genes co-regulated by IL-1β and 11β-HSD1. Of these, 204 were IL-1β-antagonizing (e.g. downregulation; BDKRB1, CCL8, CLDN1, MMP3, IL11, upregulation; ANGPTL4, GADD45B, LGR5, FSTL3 and DUSP1) and 85 were IL-1β-augmenting (e.g. downregulation; GRM1, PLCB1, AMOT, F2RL2, GPER1, upregulation; NRCAM, COL4A4, PTGDR, SERPINE1 and MT2A), indicating complex anti-inflammatory and pro-inflammatory regulation of IL-1β function by 11β-HSD1. A further 322 genes were regulated by 11β-HSD1 in an IL-1β-independent manner (e.g. downregulation; ADCY8, PTHLH, PLA2G4A, BMP2, ITGA8, upregulation; ZBTB16, LEP, FKBP5, NKD1 and MMP7). Gene over-representation analysis indicated regulation of pathways involved in extracellular matrix organization, integrin interactions, inflammation, complement and coagulation, prostaglandin synthesis, cell cycle, TGF-β signalling, hypoxia, angiogenesis and cell signalling (AP-1, PI3K-Akt, ERK, Wnt and MAPK). Genes and pathways of interest were validated by qPCR and protein expression. Our findings demonstrate for the first time the 11β-HSD1-mediated regulation of GC target genes in HDF. We report novel pro-inflammatory functions which may contribute to skin inflammatory diseases e.g. eczema. The induction of 11β-HSD1 by inflammation and subsequent inflammation-independent regulation of GC target genes in skin may drive atrophic scarring in acne. 11β-HSD1 inhibitors may represent novel therapeutic strategies to improve skin function.
07 Nov 2016 - 09 Nov 2016