Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2016) 44 P35 | DOI: 10.1530/endoabs.44.P35

SFEBES2016 Poster Presentations Adrenal and Steroids (41 abstracts)

11β-hydroxysteroid dehydrogenase type 1 mediates anti-inflammatory, pro-inflammatory and inflammation-independent effects in primary human dermal fibroblasts

Layal Abi Farraj 1 , Michael Morgan 2 , Adewonuola Alase 1 , Ian Carr 1 , Paul Stewart 1 & Ana Tiganescu 1

1University of Leeds, Leeds, UK; 2University of Oxford, Oxford, UK.

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.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

Browse other volumes

Article tools

My recent searches

No recent searches.