Abstract
Background and PurposeCatechol containing compounds have anti-inflammatory properties, yet for catecholamines these properties are modest. Since we have previously demonstrated that the synthetic dopamine derivative N-octanoyl dopamine (NOD) has superior anti-inflammatory properties compared to dopamine, we tested NOD in more detail and sought to elucidate the molecular entities and underlying mechanism by which NOD down-regulates inflammation.Experimental ApproachGenome wide gene expression profiling of human umbilical vein endothelial cells (HUVECs) was performed after stimulation with TNF-α or in the combination with NOD. Confirmation of these differences, NFκB activation and the molecular entities that were required for the anti-inflammatory properties were assessed in subsequent experiments.Key ResultsDown regulation of inflammatory genes by NOD occurred predominantly for κB regulated genes, however not all κB regulated genes were affected. These findings were explained by inhibition of RelA phosphorylation at Ser276. Leukocyte adherence to TNF-α stimulated HUVECs was inhibited by NOD and was reflected by a diminished expression of adhesion molecules on HUVECs. NOD induced HO-1 expression, but this was not required for inhibition of NFκB. The anti-inflammatory effect of NOD seems to involve the redox active catechol structure, although the redox active para-dihydroxy benzene containing compounds also displayed anti-inflammatory effects, provided that they were sufficiently hydrophobic.Conclusions and ImplicationsThe present study highlighted important mechanisms and molecular entities by which dihydroxy benzene compounds exert their potential anti-inflammatory action. Since NOD does not have hemodynamic properties, NOD seems to be a promising candidate drug for the treatment of inflammatory diseases.
Highlights
Regulated transmigration of leukocytes across the endothelial lining of the vasculature is critical to both innate and acquired immunity
Anti-inflammatory Potential of NOD To investigate the anti-inflammatory potential of N-octanoyl dopamine (NOD), we screened by genome wide gene expression profiling in human umbilical vein endothelial cells (HUVECs) for genes that were down regulated by NOD
The expression of a number of genes encoding chemokines or adhesion molecules was strongly down-regulated, and secondly, down-regulation in genes which are believed to be involved in the ubiquitin-proteasome system (UPS) was noted
Summary
Regulated transmigration of leukocytes across the endothelial lining of the vasculature is critical to both innate and acquired immunity. The inflammatory response is tightly regulated by mediators that activate the endothelium to express cell-associated adhesion molecules. Upon cytokine or chemokine activation, leukocytes firmly adhere to the endothelium [1] and subsequently leave the bloodstream using either of the two fundamentally different pathways, i.e. the para-cellular route requiring the opening of cell contacts [2] or the trans-cellular route through the body of endothelial cells [3,4,5]. Experimental Approach: Genome wide gene expression profiling of human umbilical vein endothelial cells (HUVECs) was performed after stimulation with TNF-a or in the combination with NOD. Confirmation of these differences, NFkB activation and the molecular entities that were required for the anti-inflammatory properties were assessed in subsequent experiments
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