Expression of cyclooxygenase-2 in orbital fibroadipose connective tissues of Graves’ ophthalmopathy patients

Konuk, Ece; Konuk, Onur; Mısırlıoğlu, Müge; Menevşe, Adnan; Ünal, Mehmet

doi:10.1530/eje.1.02280

Cited by 21 publications

(30 citation statements)

References 15 publications

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“…71 This enzyme is upregulated in the orbit of patients with Graves’ ophthalmopathy, 72 and T cells from such patients produce prostaglandins that induce adipogenesis in orbital fibroblasts. 73 Thyrotropin can stimulate adipogenesis in mouse embryonic stem cells, even in the absence of other adipogenic factors, suggesting that activation of the thyrotropin receptor initiates new fat-cell development.…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Graves' Ophthalmopathy

2010

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Graves’ ophthalmopathy, also called Graves’ orbitopathy, is a potentially sight-threatening ocular disease that has puzzled physicians and scientists for nearly two centuries.1–3 Generally occurring in patients with hyperthyroidism or a history of hyperthyroidism due to Graves’ disease, Graves’ ophthalmopathy is also known as thyroid-associated ophthalmopathy or thyroid eye disease, because it sometimes occurs in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis. The condition has an annual adjusted incidence rate of 16 women and 3 men per 100,000 population.4 This review explores the perplexing relationship between Graves’ ophthalmopathy, hyperthyroidism, and thyroid dermopathy, the associated skin condition. I examine clinical features, histologic findings, and laboratory studies, with an emphasis on mechanisms that could be targeted in the development of new treatments for this debilitating disease.

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Section: Molecular Mechanismsmentioning

confidence: 99%

Graves' Ophthalmopathy

2010

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“…At the heart of this response is an exaggerated induction of prostaglandin endoperoxide H synthase-2 (PGHS-2), the rate limiting, inflammatory cyclooxygenase involved in the production of PGE 2 [14]. PGHS-2 has been found over-expressed in orbital tissues from patients with TAO [15]. Moreover, both B and T cells have substantial capacity to generate PGE 2 through the induction of PGHS-2 which occurs in their activated states [16]–[18].…”

Section: Introductionmentioning

confidence: 99%

PGE2 Induces IL-6 in Orbital Fibroblasts through EP2 Receptors and Increased Gene Promoter Activity: Implications to Thyroid-Associated Ophthalmopathy

2010

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BackgroundIL-6 plays an important role in the pathogenesis of Graves' disease and its orbital component, thyroid-associated ophthalmopathy (TAO). Orbital tissues become inflamed in TAO, a process in which prostanoids have been implicated. Orbital fibroblasts both generate and respond to PGE2, underlying the inflammatory phenotype of these cells.Methodology/Principal FindingsUsing cultured orbital and dermal fibroblasts, we characterized the effects of PGE2 on IL-6 expression. We found that the prostanoid provokes substantially greater cytokine synthesis in orbital fibroblasts, effects that are mediated through cell-surface EP2 receptors and increased steady-state IL-6 mRNA levels. The pre-translational up-regulation of IL-6 results from increased gene promoter activity and can be reproduced with the PKA agonist, Sp-cAMP and blocked by interrupting the PKA pathway. PGE2-induced production of cAMP in orbital fibroblasts was far greater than that in dermal fibroblasts, resulting from higher levels of adenylate cyclase. PGE2 provokes CREB phosphorylation, increases the pCREB/CREB ratio, and initiates nuclear localization of the pCREB/CREB binding protein/p300 complex (CBP) preferentially in orbital fibroblasts. Transfection with siRNAs targeting either CREB or CBP blunts the induction of IL-6 gene expression. PGE2 promotes the binding of pCREB to its target DNA sequence which is substantially greater in orbital fibroblasts.Conclusion/SignificanceThese results identify the mechanism underlying the exaggerated induction of IL-6 in orbital fibroblasts and tie together two proinflammatory pathways involved in the pathogenesis of TAO. Moreover, they might therefore define an attractive therapeutic target for the treatment of TAO.

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“…Recently, it has been shown that selenium was able to reduce H 2 O 2 -mediated expression of COX-2 in vascular endothelial cells by inhibiting the p38 MAPK pathway [51]. …”

Section: Mechanisms Of Selenium Action In Gd and Gomentioning

confidence: 99%

The Evolving Role of Selenium in the Treatment of Graves' Disease and Ophthalmopathy

Duntas

2012

Journal of Thyroid Research

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Graves' disease (GD) and ophthalmopathy (GO) are organ-specific autoimmune-inflammatory disorders characterized by a complex pathogenesis. The inflammatory process is dominated by an imbalance of the antioxidant-oxidant mechanism, increased production of radical oxygen species (ROS), and cytokines which sustain the autoimmune process and perpetuate the disease. Recently, selenium, which is a powerful antioxidant, has been successfully applied in patients with mild GO, slowing the progression of disease, decreasing the clinical activity score, and appreciably improving the quality of life. The mechanisms of selenium action are variable. The aim of this review is to summarize the actions of selenium in GD and GO. Selenium as selenocysteine is incorporated in selenoproteins, such as glutathione peroxidase which catalyzes the degradation of hydrogen peroxide and lipid hydroperoxide that are increasingly produced in hyperthyroidism. Moreover, selenium decreases the formation of proinflammatory cytokines, while it contributes, in synergy with antithyroid drugs, to stabilization of the autoimmune process in GD and alleviation of GO. It is now to be clarified whether enforced nutritional supplementation has the same results and whether prolonging selenium administration may have an impact on the prevention of disease.

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Expression of cyclooxygenase-2 in orbital fibroadipose connective tissues of Graves’ ophthalmopathy patients

Cited by 21 publications

References 15 publications

Graves' Ophthalmopathy

Graves' Ophthalmopathy

PGE2 Induces IL-6 in Orbital Fibroblasts through EP2 Receptors and Increased Gene Promoter Activity: Implications to Thyroid-Associated Ophthalmopathy

The Evolving Role of Selenium in the Treatment of Graves' Disease and Ophthalmopathy

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