Endocrine Abstracts

Ocular and orbital tissues are extremely susceptible to damage by immune-mediated inflammatory conditions, such as thyroid-associated-ophthalmopathy (TAO). Recent studies have implicated fibroblasts in the development of chronic inflammation. Once activated by inflammatory cytokines, fibroblasts secrete pro-inflammatory cytokines perpetuating the inflammatory process, causing significant tissue damage. Synovial fibroblasts have been reported to regulate inflammation by increasing local cortisol production via oxo-reductase activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This study characterised the expression and activity of 11β-HSD1 in ocular fibroblasts and evaluated its regulation by pro- and anti-inflammatory cytokines.

Primary fibroblast cultures were developed from normal human conjunctival, corneal, scleral and orbital fat tissues (ethical approval obtained). 11β-HSD1 activity assays carried out following 24 h incubation with tumour necrosis factor-α (TNFα), interleukin-4 (IL-4), interleukin-6 (IL-6), interferon-γ (IFNγ), and transforming growth factor-β (TGFβ), illustrated 11β-HSD1 oxo-reductase activity in fibroblasts from all four ocular tissues, with a significant induction in enzyme activity from TNFα-treated fibroblasts. Increased gene expression of 11β-HSD1, glucocorticoid receptor α (GRα), hexose-6-phosphate dehydrogenase (H6PDH), IL-6, TGFβ₁, and interleukin 1β (IL-1β) was demonstrated in fibroblasts treated with TNFα and IL-6, by real-time PCR. Analysis of the culture supernatant by Multiplex ELISA, illustrated repression in the synthesis of pro-inflammatory cytokines (IL-6, IL-8, TNFα, and IFNγ), following the induction of 11β-HSD1.

This study has identified an increase in both expression and activity of 11β-HSD1 in response to pro-inflammatory cytokines. This demonstrates intrinsic regulation of inflammation by increasing cortisol levels within the stromal microenvironment. Consequently, this isozyme may be a potential therapeutic target in conditions such as TAO, due to its regulatory role in the control of inflammation.