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

BACKGROUND: IL-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 PGE(2), underlying the inflammatory phenotype of these cells. METHODOLOGY/PRINCIPAL FINDINGS: Using cultured orbital and dermal fibroblasts, we characterized the effects of PGE(2) on IL-6 expression. We found that the prostanoid provokes substantially greater cytokine synthesis in orbital fibroblasts, effects that are mediated through cell-surface EP(2) 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. PGE(2)-induced production of cAMP in orbital fibroblasts was far greater than that in dermal fibroblasts, resulting from higher levels of adenylate cyclase. PGE(2) 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. PGE(2) promotes the binding of pCREB to its target DNA sequence which is substantially greater in orbital fibroblasts. 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 TAO. Moreover, they might therefore define an attractive therapeutic target for the treatment of TAO

Melolabial fold interpolated flap for reconstruction of complex nasal defects Retalho interpolado do sulco melolabial para reconstrução de defeitos complexos do nariz

Complex surgical nasal defects are often technically difficult. We report the case of a 71-year old male diagnosed with a malignant melanoma (animal type; Breslow 1.5; Clark IV) on the right nasal ala. Radial excision with margins of approximately 1.5cm was performed, creating a complex full-thickness surgical defect involving the free wall and margin of the right nasal ala, the right soft triangle, nasal lobe and columella, which was reconstructed using a melolabial interpolated flap, with highly satisfactory final esthetic result. Interpolated flaps are viable surgical options for the reconstruction of surgical defects for which local flaps and skin grafts are not suitable.<br>A reconstrução de defeitos cirúrgicos complexos do nariz é, por norma, tecnicamente difícil. Apresentamos um doente do sexo masculino, de 71 anos, referenciado após biopsia excisional de melanoma maligno de tipo animal (Breslow 1,5 mm, Clark IV) da asa direito do nariz. O alargamento excisional com margem de 1,5 cm originou um defeito complexo envolvendo a asa nasal direita, o triângulo mole direito, o lobo nasal e a columela, que foi reconstruído por retalho interpolado do sulco melolabial, com resultado cosmético final bastante satisfatório. Os retalhos interpolados são opções cirúrgicas eficazes para reconstrução de defeitos cutâneos para os quais a realização de retalhos locais não é possível e a colocação de enxertos inviabiliza um resultado cosmético aceitável