Impact of Resolvin D1 on RAGE and NF-kB gene expression in human monocytes
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BACKGROUND AND OBJECTIVES: Diabetes mellitus involves inflammatory processes due to chronic hyperglycemia and accumulation of Advanced Glycation Endproducts (AGE). AGEs have been shown to impact the monocyte phenotype, shifting towards a more pro-inflammatory phenotype. Activation of immune cells can lead to destruction of the healthy tissues. Active agonists of resolution phase of the inflammation such as resolvinshave anti-inflammatory, pro-resolving actions. Studies have shown that these actions can contribute to suppression of inflammation and accelerate the healing process. In this study, we aimed to elucidate the mechanism of Resolvin Dl (RvDl) on the expression of receptor for AGE (RAGE) and NF-[kappa]B as these are both critical signaling pathways involved in downstream gene expression. MATERIALS AND METHODS: Primary peripheral blood human monocytes were isolated from healthy subjects. Cells were challenged under five conditions: normal glucose level (5.5mM), high glucose level (25mM), S100b (AGE) (5[mega]g/ml), and a combination of high glucose and S100b, as well as a blank media negative control. Cells were challenged for 6 and 24 hours. Another group of monocytes were challenged under the same conditions listed above. In addition, they were treated with RvD1 (100ng/ml). Total RNA was isolated and quantitative PCR was performed to determine levels of RAGE and NF-[kappa]B expression. RESULTS: In the RvD1 untreated group, a 4-fold increase of RAGE gene expression was observed in the S 100b treated group, while NF-[kappa]B gene expression was increased slightly compared to the control. This change was observed more at the 24-hour time point. In the RvD1 treated group, NF-[kappa]B gene expression was reduced among all groups compared to the negative control at both 6 and 24hour time points. RAGE expression in RvD1 treated groups was also dramatically decreased compared to the control, seen in all treatment groups except the S 100b-24hour. Treatment with RvD1 dramatically reduces both RAGE and NF-[kappa]B gene expression levels after 24 hours exposure under all treatment conditions. This is especially obvious in the S 100b-24-hour treatment group. CONCLUSION AND CLINICAL SIGNIFICANCE:Chronic hyperglycemia and AGE accumulation are considered as powerful contributing factors to modify the monocyte phenotype in diabetic patients, which increase the level of pro-inflammatory cytokine production that is involved in various inflammatory reactions. RvD1 has the potential to regress the diabetes inflammatory nature by suppressing expression of the genes responsible for increased production of the cytokines.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact firstname.lastname@example.org.Dissertation (MSD) --Boston University, Henry M. Goldman School of Dental Medicine, 2013 (Department of Oral Biology and Periodontology).Includes bibliographic references: leaves 54-62.
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