The role of 11β-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy

Abstract

Context: Thyroid-associated ophthalmopathy (TAO) is a sight-threatening autoimmune disease in which de novo adipogenesis has been identified as a fundamental pathogenic mechanism. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) increases cortisol bioavailability and is pivotal in mediating glucocorticoid responses in adipose tissue and inflammation. Objective: In this study we characterize 11β-HSD1 as a determinant of the adipogenic and inflammatory pathways in TAO orbital fat (OF) compared with normal OF. Patients and Methods: OF was harvested from 46 TAO and 44 control patients undergoing orbital surgery. Samples were examined by a combination of immunohistochemistry, real-time RT-PCR, primary cell culture, specific enzyme assays, colorimetric proliferation assays, and bead-based ELISA. Results: Glucocorticoid (glucocorticoid receptor-α,11β-HSD1, hexose-6-phosphate dehydrogenase) and inflammatory cytokines (IL-1β, IL-1 receptor, IL-6, TNF-α, TNF-α inductible protein, TGF-β2) target genes together with markers of late adipocyte differentiation (fatty-acid-binding-protein-4, glycerol-6-phosphate-dehydrogenase) were highly expressed in TAO whole OF (P < 0.05) compared with controls. Primary cultures of TAO OF stromal cells demonstrated greater 11β-HSD1 oxoreductase activity (P < 0.05), which was regulated by cytokines, most notably TNF-α (P < 0.01), compared with controls. Activity increased across differentiation, and this was most marked in TAO cells (P < 0.01). Similarly, stromal cell proliferation was limited by incubation with cortisol in TAO cells only. Furthermore, cortisone decreased IL-6 (P < 0.005), IL-8 (P < 0.05), and macrophage chemoattractant protein-1 (P < 0.05) production by cultured TAO cells only, an effect that was abrogated by inhibition of 11β-HSD1. Conclusions: Induction of 11β-HSD1 activity and expression by inflammatory cytokines (TNF-α, IL-6) may enhance orbital adipocyte differentiation (adipogenesis) and limit proliferation in TAO. 11β-HSD1 may also have a role in regulating the local orbital inflammatory response. Copyright © 2010 by The Endocrine Society.