Abstract
Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed. Additionally, MDDCs treated with alcohol were assessed using qRT-PCR, western blot, and fluorometric assay. The functional effects of alcohol-induce oxidative stress were measured in vitro using PCR array and in silico using gene expression network analysis. Our findings show, for the first time, that MDDCs from self-reported alcohol users have higher levels of class I HDACs compare to controls and alcohol treatment in vitro differentially modulates HDACs expression. Further, HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs and modulated alcohol-induced oxidative stress related genes expressed by MDDCs. In silico analysis revealed new target genes and pathways on the mode of action of alcohol and HDACi. Findings elucidating the ability of alcohol to modulate class I HDACs may be useful for the treatment of alcohol-induced oxidative damage and may delineate new potential immune-modulatory mechanisms.
Highlights
Alcohol consumption has been reported to impair the development of both innate and adaptive immune responses [1], the effects of alcohol on the innate immune system are controversial
In the current study, we present a novel approach combining ex vivo, in vitro, and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of histone deacetylases (HDACs) expressed by monocytederived dendritic cells (MDDCs) in the peripheral blood
When the cells were treated with the HDAC inhibitors (HDACi), trichostatin A (TSA) and MGCD0103, there was a reduction in viability across the HDACi treated groups compared to the untreated control by 48 hrs. and this reduction was more profound on the MGCD0103 treated cells (Fig 1D)
Summary
Alcohol consumption has been reported to impair the development of both innate and adaptive immune responses [1], the effects of alcohol on the innate immune system are controversial. Dendritic cells (DCs) play a crucial role during inflammation and have been shown to be affected during alcohol abuse. Acute alcohol consumption has been reported to inhibit monocytes and dendritic cell functions [5]. Immune responses induced by chronic alcohol consumption in mice [6] and humans [7] are suggested to be partly due to impaired DC function [8]. There is substantial evidence supporting the role of DCs on alcohol-induced inflammation and liver injury [8], the exact mechanisms by which alcohol leads to immune defects are unknown
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