Unknown,Transcriptomics,Genomics,Proteomics

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The expression of inflammatory genes in endothelial cells is inhibited by N-octanoyl dopamine via modulation of the NFkB pathway

ABSTRACT: Background: Dopamine has intrinsic receptor-independent anti-inflammatory properties when used at high concentrations. Since cellular uptake of N-octanoyl dopamine (NOD) is far better than of dopamine, NOD might display anti-inflammatory effects already at relative low concentrations. The present study was conducted to assess the anti-inflammatory potential of NOD and to elucidate how this was mediated. Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-Î± in the presence of various NOD concentrations. Affymetrix gene expression profiling (GEP), Western blotting, adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells and NFÎºB activation was studied. Compounds that were structurally related to NOD were used to address the molecular entities within NOD that were required for its anti-inflammatory properties. Results: GEP revealed that NOD down-regulates a wide range of pro-inflammatory mediators. Down-regulation of adhesion molecules was confirmed at the protein level and resulted in a decreased adhesion of PBMC to endothelial cells under static and flow conditions. NOD inhibited NFÎºB independently of IÎºBÎ± degradation. Inhibition was associated with an overall decrease in p65 expression and a significant decrease in p65 phosphorylation at Ser276. De novo protein synthesis was not required for inhibition and was not mediated via HO-1. Redox activity and hydrophobicity of NOD seemed to be important entities for its anti-inflammatory properties. Conclusion: Our data demonstrate that NOD has potent anti-inflammatory effects through its action on NFÎºB. Unlike dopamine, NOD has no adverse effects on blood pressure, making it a promising candidate drug to reduce excessive inflammation occurring under various pathological conditions. A total of 6 different HUVEC lines were used, n=3 for each group (TNF or TNF+ NOD).

ORGANISM(S): Homo sapiens

SUBMITTER: Benito Yard

PROVIDER: E-GEOD-34059 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In addition to their role in the development and function of the reproductive system, estrogens have significant anti-inflammatory properties. Although both estrogen receptors (ERs) can mediate anti-inflammatory actions, ERbeta is a more desirable therapeutic target because ERalpha mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ERbeta agonists have beneficial effects in preclinical models involving inflammation without causing growth-promoting effects on the uterus or mammary gland. However, their mechanism of action is unclear. The purpose of this study was to use microarray analysis to determine whether ERbeta-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-alpha in human osteosarcoma U2OS cells expressing ERbeta. Estradiol treatment significantly reduced the activation by TNF-alpha on 18 genes via ERbeta or ERalpha. Most repressed genes were inflammatory genes, such as TNF-alpha, IL-6, and CSF2. Three ERbeta-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ERbeta-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ERbeta-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ERbeta-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ERbeta-selective estrogens in animal models are due to transcriptional repression of proinflammatory genes. These compounds might represent a new class of drugs to treat inflammatory disorders. Experiment Overall Design: Expression of ER in the U2OS-ERÃ cells was induced with doxycycline. The cells were treated in the absence or presence of 10 nM E2 for 18 h followed by incubation with TNF-{alpha} for 1 h. Total RNA were extracted, followed by cRNA labelling, and hybridization of fragmented samples to the U95Av2 arrays (n = 3 for untreated, n = 4 for TNF-{alpha}-treated, n = 4 for TNF-{alpha}- and E2-treated samples). The data were analyzed using the Microarray Suite Version 5.0 with the default parameters. The comparative data generated for each treated group were analyzed further in Microsoft Excel. TNF-{alpha}-induced genes were selected for further analysis only if they had a 1.2 signal log ratio mean value (2.3-fold change) and were statistically significant (p < 0.05) in at least three separate experiments.

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The expression of inflammatory genes in endothelial cells is inhibited by N-octanoyl dopamine via modulation of the NFkB pathway

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