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This version published online on October 30, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0873
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Submitted on April 24, 2009
Accepted on October 6, 2009

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

Jeremy W. Tomlinson, Omar M. Durrani, Iwona J. Bujalska, Laura L. Gathercole, Paul J. Tomlins, Tristan T. Q. Reuser, Geoffrey E. Rose, S. John Curnow, Paul M. Stewart, Elizabeth A. Walker, and Saaeha Rauz*

Department of Endocrinology (J.W.T., I.J.B., L.L.G., P.M.S., E.A.W.), School of Clinical and Experimental Medicine, and Academic Unit of Ophthalmology (O.M.D., P.J.T., T.T.Q.R., S.J.C., S.R.), School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and Moorfields Eye Hospital (G.E.R.), London EC1V 2PD, United Kingdom

* To whom correspondence should be addressed. E-mail: s.rauz{at}bham.ac.uk.

Context: Thyroid-associated ophthalmopathy (TAO) is a sight-threatening autoimmune disease in which de novo adipogenesis has been identified as a fundamental pathogenic mechanism. 11{beta}-Hydroxysteroid dehydrogenase 1 (11{beta}-HSD1) increases cortisol bioavailability and is pivotal in mediating glucocorticoid responses in adipose tissue and inflammation.

Objective: In this study we characterize 11{beta}-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-{alpha},11{beta}-HSD1, hexose-6-phosphate dehydrogenase) and inflammatory cytokines (IL-1{beta}, IL-1 receptor, IL-6, TNF-{alpha}, TNF-{alpha} inductible protein, TGF-{beta}2) 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 11{beta}-HSD1 oxoreductase activity (P < 0.05), which was regulated by cytokines, most notably TNF-{alpha} (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 11{beta}-HSD1.

Conclusions: Induction of 11{beta}-HSD1 activity and expression by inflammatory cytokines (TNF-{alpha}, IL-6) may enhance orbital adipocyte differentiation (adipogenesis) and limit proliferation in TAO. 11{beta}-HSD1 may also have a role in regulating the local orbital inflammatory response.






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