Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-Derived Dendritic Cells
Abstract
The effects of alcohol abuse are multi-dimensional since alcohol is widely known to affect both the innate and adaptive immune systems. Recently, epigenetics has come into focus and has been implicated in many diseases as well as substance abuse disorders. Therefore, research efforts of understanding the epigenetic mechanisms underlying substance abuse effects including alcohol abuse have become more predominant. In our laboratory, we have studied different epigenetic changes induced by alcohol exposure including regulation of histone deacetylases (HDACs), histone quantity, and histone modifications such as acetylation and deacetylation. We have observed differential effects of acute and chronic alcohol exposure in human monocyte-derived dendritic cells (MDDCs) wherein our laboratory previously found that HDACs were modulated in MDDCs treated acutely with alcohol in vitro, and in MDDCs from alcohol users. Our previous work has also demonstrated that alcohol consumption affects the dendritic cell function by modulating inflammatory markers and cannabinoid receptors such as CB2 and GPR55 through epigenetic modifications. For instance, chronic alcohol exposure upregulates histone (H) 4 acetylation at lysine 12 (H4k12ac) and acute alcohol effects on histone acetylation are associated with an increase in GPR55 expression. The hypothesis of the study is that chronic alcohol modulates human MDDC function through epigenetic mechanisms. Therefore, the primary objective of this research project is to elucidate novel pathways involving histone post-translational modifications due to chronic alcohol exposure in human dendritic cells. For this study, monocytes isolated from commercially available human buffy coats were differentiated into MDDCs, which were treated with chronic alcohol levels of 0.1 % (100mg/dL) and 0.2 % (200mg/dL) for 5 days in the presence or absence of the histone acetyltransferase inhibitor NU9056 (50nM) or the GPR55 antagonist CID16020046 (5µM). Results showed that chronic alcohol levels upregulated H4K12ac in MDDCs and this was associated with a concomitant increase in GPR55 gene and protein expression. Further, NU9056 and CID16020046 were able to reduce alcohol-induced inflammatory chemokine MCP-2 and reactive oxygen species production indicating that H4K12ac may be an inflammation and oxidative stress regulator. Additionally, NU9056 and CID16020046 could potentially reduce alcohol-induced inflammation and serve as potential therapeutic targets for alcohol use disorders.
Subject Area
Immunology|Medicine|Health sciences
Recommended Citation
Parira, Tiyash, "Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-Derived Dendritic Cells" (2018). ProQuest ETD Collection for FIU. AAI27736564.
https://digitalcommons.fiu.edu/dissertations/AAI27736564