The Role of 11ß-Hydroxysteroid Dehydrogenase 1 in Adipogenesis in Thyroid-Associated Ophthalmopathy

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 1; pp. 398 - 406
• Main Authors: Tomlinson, Jeremy W, Durrani, Omar M, Bujalska, Iwona J, Gathercole, Laura L, Tomlins, Paul J, Reuser, Tristan T. Q, Rose, Geoffrey E, Curnow, S. John, Stewart, Paul M, Walker, Elizabeth A, Rauz, Saaeha
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01.01.2010; Copyright by The Endocrine Society
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-0873

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. Thyroid-associated ophthalmopathy is associated with increased local glucocorticoid regeneration through the activity of 11β-hydroxysteroid dehydrogenase type 1 that drives orbital adipogenesis.