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


OBJECTIVE
In this study we characterize 11beta-HSD1 as a determinant of the adipogenic and inflammatory pathways in TAO orbital fat (OF) compared with normal OF.


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,11beta-HSD1, hexose-6-phosphate dehydrogenase) and inflammatory cytokines (IL-1beta, IL-1 receptor, IL-6, TNF-alpha, TNF-alpha inductible protein, TGF-beta2) 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 11beta-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 11beta-HSD1.


CONCLUSIONS
Induction of 11beta-HSD1 activity and expression by inflammatory cytokines (TNF-alpha, IL-6) may enhance orbital adipocyte differentiation (adipogenesis) and limit proliferation in TAO. 11beta-HSD1 may also have a role in regulating the local orbital inflammatory response.
Tomlinson
Jeremy W
JW
Department of Endocrinology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, BirminghamB15 2TT, United Kingdom.
Durrani
Omar M
OM
Bujalska
Iwona J
IJ
Gathercole
Laura L
LL
Tomlins
Paul J
PJ
Reuser
Tristan T Q
TT
Rose
Geoffrey E
GE
Curnow
S John
SJ
Stewart
Paul M
PM
Walker
Elizabeth A
EA
Rauz
Saaeha
S
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D050156:Adipogenesis / Q000235:genetics* / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology; D049970:Graves Ophthalmopathy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009915:Orbit / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology
D005938:Glucocorticoids; D018836:Inflammation Mediators; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1