and CCAAT/enhancer-binding proteins a and b were all strongly enhanced in cells treated with either rosiglitazone or IL-1b. The protein levels were all further increased by the combination of rosiglitazone and IL-1b. Quercetin dose-dependently and significantly attenuated the expression of PPARc, C/EBPa, and C/EBPb in differentiated fibroblasts treated with rosiglitazone, with 15516710” or without IL-1b. Effect of Quercetin in Graves’ Orbitopathy 5 October 2011 | Volume 6 | Issue 10 | e26261 Effect of Quercetin in Graves’ Orbitopathy mRNA for IL-6 and IL-8 than inactive GO tissues. In our study, we found that quercetin inhibits ICAM-1, IL-6, IL-8, and COX-2 gene expression in cell strains from GO donors, and it also suppresses IL-1b-induced ICAM-1, IL-6, and IL-8 mRNA expression in cell strains from GO and normal donors. Considering the possible roles of ICAM-1, IL-6, IL-8, and COX-2 in the immunologic pathogenesis of GO, prevention of expression of these molecules could be an effective treatment for GO. There are conflicting reports concerning the expression of COX-1 and -2 in ” orbital fibroblasts. In our study, we observed that COX-2 mRNA expression is significantly inhibited by quercetin treatment in GO cell strains. We found that COX-2 mRNA is upregulated by IL-1b in both GO and normal cells; however, quercetin did not suppress the IL-1b-induced increase of COX-2 gene expression. Of note, the relative expression of COX2 mRNA stimulated by IL-1b was lower than that of ICAM-1, IL6, and IL-8 in all cell cultures. We expected to observe a more significant upregulation of proinflammatory molecule gene expression by IL-1b or TNF-a in GO cell strains than in normal cells, but we obtained similar results in both, in agreement with previous reports. The orbital fibroblast cells used in our experiments were all derived from orbital G5555 tissues 
of fat-predominant patients with minimally active GO. All seven GO patients were biochemically euthyroid with anti-hyperthyroid medications at the time of surgery, and their clinical activity scores were three or less. This could explain the similar responses of GO and normal cells to IL-1b, and this was the reason we used IL-1b to stimulate inflammation and hyaluronan production in orbital fibroblasts from both GO and normal donors. However, in naive normal cells without IL-1b stimulation, mRNAs of proinflammatory molecules were not detectable and not affected by quercetin pretreatment, whereas those molecules were expressed at detectable levels, and their expression was suppressed by quercetin, in GO cells. Although the GO patients in our study had minimal inflammatory activity by clinical criteria, the enlarged fatty tissue compressed under pressure in the fixed bony orbits of GO patients could be exposed to more inflammatory local conditions than normal orbital fatty tissues. Quercetin significantly attenuated the IL-1b- or TNF-a-induced activity measured with an NF-kB-dependent reporter construct, and it also inhibited IL-1b-induced NF-kB nuclear translocation, suggesting that the anti-inflammatory action of quercetin may be mediated by the NF-kB pathway. In our study, an NF-kB inhibitor suppressed the IL-1b-induced ICAM-1 and COX-2 expression, but not that of IL-6 and IL-8. This indicates that different mechanisms are involved in the anti-inflammatory action of quercetin. We have also tested the effect of quercetin on the expression of IL-10, an anti-inflammatory cytokine repressing the inflammatory cytokines s
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