Abstract
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.
Highlights
In the autoimmune thyroid syndrome, Graves’ disease, the orbit becomes inflamed and undergoes extensive tissue remodeling, a condition known as thyroid-associated ophthalmopathy2 (TAO) [1,2]
Conclusion/Significance: These 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 thyroidassociated ophthalmopathy (TAO)
IL-6 production in untreated orbital fibroblasts occurred at a very low level but when prostaglandin E2 (PGE2) was added to the culture medium, levels of the cytokine were increased substantially
Summary
In the autoimmune thyroid syndrome, Graves’ disease, the orbit becomes inflamed and undergoes extensive tissue remodeling, a condition known as thyroid-associated ophthalmopathy (TAO) [1,2]. Hiromatsu et al [7] studied the cytokine profiles of patients with Graves’ disease and TAO. They found that extra-ocular eye muscle and orbital fat from these individuals express high levels of IL-6 mRNA and that orbital volumes correlated positively with levels of these transcripts. These findings may prove relevant to antibody-driven autoimmune diseases like Graves’ disease since IL-6 supports B lymphocyte and plasma cell function and is a recognized cofactor in fat metabolism [8,9]. Orbital fibroblasts both generate and respond to PGE2, underlying the inflammatory phenotype of these cells
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