Endocrine Abstracts (2015) 38 OC3.3 | DOI: 10.1530/endoabs.38.OC3.3

11[beta]-HSD1-mediated decrease in COX2 expression is abrogated by hypoxia in human dermal fibroblasts

Ana Tiganescu, Miriam Wittmann, Ann Morgan & Paul Stewart


University of Leeds, Leeds, UK.


Chronic wounds contribute significantly to patient morbidity, mortality and associated healthcare costs. Glucocorticoid (GC) excess and hypoxia are both associated with impaired wound healing (WH) outcomes. The cyclooxygerase 2 (COX2) pathway is an integral component of inflammation and WH. Locally, GC availability is regulated by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which generates cortisol from inactive cortisone. Although we recently demonstrated that 11β-HSD1 increases during the inflammatory phase of mouse skin WH, a functional role for 11β-HSD1 in human skin remains to be established. Primary human dermal fibroblasts (HDF) were incubated±IL1β, cortisol, and cortisone for 96 h. Ten microgram/ml IL1β increased COX2 mRNA expression (by qPCR) by 36-fold** (**P<0.01), with 50 nM cortisol reducing expression by 64%**. Cortisol decreased IL1β-mediated COX2 expression by 86%**, this was prevented by 5 μM RU486** (GC receptor antagonist). Importantly, 200 nM cortisone also reduced IL1β-mediated COX2 expression by 80%** (time-dependently), this was prevented (dose-dependently) by a selective 11β-HSD1 inhibitor. However, under hypoxic conditions (1% oxygen) cortisone was unable to suppress IL1β-mediated COX2 expression. Moreover, IL1β increased 11β-HSD1 expression by 24- to ninefold** and hypoxia further enhanced this by 86%**. These data are supported by 11β-HSD1 activity assays (using trace amounts of tritium-labelled cortisone substrate), which indicated minimal cortisol generation at baseline (0.1 nM/h). IL1β induced 11β-HSD1 activity by sixfold**, generating 50 nM cortisol in 72 h (cortisol dose–response experiments revealed a minimal concentration of 25–50 nM for GC receptor activation). IL1β-mediated 11β-HSD1 activity further increased by 68%** (1.2 nM cortisol/h) under hypoxic conditions and was undetectable during co-incubation with 11β-HSD1 inhibitor. In summary, we demonstrate that the previously unreported 11β-HSD1-mediated regulation of GC target genes in HDF (e.g. COX2) may be limited in a hypoxic environment. Our findings also suggest a novel synergy between inflammation and hypoxia may drive local GC excess through increased 11β-HSD1, contributing to wound chronicity.

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