The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy.
CONTEXT: 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 gluco...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2010
|
| _version_ | 1797102528524976128 |
|---|---|
| author | Tomlinson, J Durrani, O Bujalska, I Gathercole, L Tomlins, P Reuser, T Rose, G Curnow, S Stewart, P Walker, E Rauz, S |
| author_facet | Tomlinson, J Durrani, O Bujalska, I Gathercole, L Tomlins, P Reuser, T Rose, G Curnow, S Stewart, P Walker, E Rauz, S |
| author_sort | Tomlinson, J |
| collection | OXFORD |
| description | CONTEXT: 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. 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,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. |
| first_indexed | 2024-03-07T06:07:11Z |
| format | Journal article |
| id | oxford-uuid:ee3dbd26-972d-40c0-8cb5-02c75e058cd0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:07:11Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:ee3dbd26-972d-40c0-8cb5-02c75e058cd02022-03-27T11:31:17ZThe role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ee3dbd26-972d-40c0-8cb5-02c75e058cd0EnglishSymplectic Elements at Oxford2010Tomlinson, JDurrani, OBujalska, IGathercole, LTomlins, PReuser, TRose, GCurnow, SStewart, PWalker, ERauz, SCONTEXT: 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. 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,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. |
| spellingShingle | Tomlinson, J Durrani, O Bujalska, I Gathercole, L Tomlins, P Reuser, T Rose, G Curnow, S Stewart, P Walker, E Rauz, S The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. |
| title | The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. |
| title_full | The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. |
| title_fullStr | The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. |
| title_full_unstemmed | The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. |
| title_short | The role of 11beta-hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid-associated ophthalmopathy. |
| title_sort | role of 11beta hydroxysteroid dehydrogenase 1 in adipogenesis in thyroid associated ophthalmopathy |
| work_keys_str_mv | AT tomlinsonj theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT durranio theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT bujalskai theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT gathercolel theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT tomlinsp theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT reusert theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT roseg theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT curnows theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT stewartp theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT walkere theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT rauzs theroleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT tomlinsonj roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT durranio roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT bujalskai roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT gathercolel roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT tomlinsp roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT reusert roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT roseg roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT curnows roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT stewartp roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT walkere roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy AT rauzs roleof11betahydroxysteroiddehydrogenase1inadipogenesisinthyroidassociatedophthalmopathy |