Management of Graves' orbitopathy (GO) is challenging, as no reliable, specific, and safe medical therapeutic agents have yet been developed. We investigated the effect of quercetin in primary cultured orbital fibroblasts from GO, targeting pathways of inflammation, aberrant accumulation of extracellular matrix macromolecules, and adipose tissue expansion. Quercetin significantly attenuated intercellular adhesion molecule-1 (ICAM-1), interleukin (IL) -6, IL-8, and cyclooxygenase (COX) -2 mRNA expression, and inhibited IL-1β-induced increases in ICAM-1, IL-6, and IL-8 mRNA. Increased hyaluronan production induced by IL-1β or tumor necrosis factor-α was suppressed by quercetin in a dose- and time-dependent manner. Treatment with noncytotoxic doses of quercetin inhibited accumulation of intracytoplasmic lipid droplets and resulted in a dose-dependent decrease in expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, and C/EBPβ proteins. In conclusion, inhibition of inflammation, hyaluronan production, and adipogenesis by the natural plant product quercetin in vitro provides the basis for further study of its potential use in the treatment of GO.

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Cigarette smoking is known to aggravate Graves' orbitopathy (GO) severity by enhancing adipogenesis. We investigated the effect of quercetin, an antioxidant, on adipocyte differentiation induced by cigarette smoke extract (CSE) in primary cultured orbital fibroblasts (OFs) from GO patients. Freshly prepared CSE was added to the cells and H 2 O 2 was used as a positive control. Intracellular reactive oxygen species (ROS) generation and adipogenesis were measured. The expressions of proteins peroxisome proliferator-activated receptor (PPAR) g, CCAAT-enhancer-binding proteins (C/EBP) a and b, and heme oxygenase-1 (HO-1), an antioxidant enzyme, were examined during adipogenic differentiation. In result, CSE and H 2 O 2 dose-dependently stimulated intracellular ROS production in normal and Graves' OFs. The effect of 2% CSE was similar to that of 10 mM H 2 O 2 ; both concentrations were noncytotoxic and were used throughout the experiment. Quercetin pretreatment reduced the ROS generation stimulated by either CSE or H 2 O 2 in preadipocyte OFs. CSE and H 2 O 2 stimulated adipocyte differentiation in cultured OFs. The addition of quercetin (50 or 100 mM) suppressed adipogenesis. Quercetin also suppressed ROS generation in differentiating OFs during adipogenesis stimulated by CSE and H 2 O 2 . Additionally, the expressions of PPARg, C/EBPa, and C/EBPb proteins were reduced in the quercetin-treated OFs. Quercetin also reduced the CSE-and H 2 O 2 -induced upregulation of ROS and HO-1 protein in differentiated OFs and preadipocyte OFs. As shown in this study, quercetin inhibited adipogenesis by reducing ROS in vitro, supporting the use of quercetin in the treatment of GO. IntroductionOxidative stress is implicated in the pathogenesis of Graves' orbitopathy (GO), and cigarette smoking is known to be a major environmental factor that affects GO. Cigarette smoking has been shown to influence the incidence, severity, and responses to treatment of GO, and appears to do so in a dose-dependent and temporal manner. Reportedly, smokers with Graves' disease are approximately five times more likely to develop GO than Journal of Endocrinology Research J S YOON, H J LEE and othersTreatment of GO by quercetin, an antioxidant 216:2 145-156

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