CD4+ T cell depletion is a major component of the multiple detrimental effects of chronic alcohol consumption on the immune system. Chronic alcohol abuse leads to abnormal S-adenosylmethionine (SAM) metabolism and decreased hepatic SAM levels. Our earlier work in CD4+ T cells has demonstrated that ethanol significantly decreases lymphocytic methionine adenosyltransferase (MAT II) expression and activity, with resultant SAM deficiency, and also increases activation-induced Fas-mediated apoptotic death. Notably, exogenous SAM supplementation restored intracellular SAM and prevented apoptotic signaling and death in ethanol treated CD4+ T cells. These data not only showed a causal role for SAM deficiency in ethanol mediated apoptotic death but also provided the proof-of-concept for SAM therapy in preventing alcohol induced CD4+ T cell depletion and immune suppression. SAM functions as the critical methyl donor during epigenetic regulation leading to enzymatic modification of histones and DNA cytosine residues. Our recent work on ethanol treated primary human CD4+ T cells in vitro as well as CD4+ T cells obtained from alcoholic patients has provided convincing preliminary data showing that ethanol exposure can cause transcriptionally permissive modifications in histones associated with the FasL promoter. These histone modifications enhance transcriptional activation of the FasL promoter resulting in increased mRNA expression, apoptotic signaling and cell death. The overall objective of this proposal is to systematically examine genome wide as well as gene specific (promoter associated) histone and DNA modifications involved in alcohol-mediated apoptotic signaling and death in CD4+ T cells. We expect that the results of our study will provide critical molecular insights in the alcohol-induced immunotoxicity of CD4+ T cells. We predict that results from this research will also provide important insights into immune dysfunction/CD4+ T cell loss in alcohol consuming HIV-infected patients.
The specific aims of this translational proposal investigating the epigenetic mechanisms involved in aberrant apoptotic signaling and cell death of CD4+ T lymphocytes in alcoholic patients are:
Aim 1 : Examine the effects of alcohol on cellular SAM levels, global histone and DNA modifications and apoptotic cell death in CD4+ T cells.
Aim 2 : Determine the gene specific (promoter associated) histone and DNA modifications occurring in response to alcohol-mediated SAM deficiency that impact the expression of apoptotic genes relevant to CD4+ T cell survival.
Alcohol abuse continues to be a significant burden on the US healthcare system. The studies proposed here will examine epigenetic modifications involved in alcohol-induced depletion of CD4+ T lymphocytes using both a genome-wide approach, as well as a hypothesis-based candidate gene approach. The data obtained from these studies will yield mechanistic insights underlying alcohol induced immune suppression and how alcohol may further depress immune function in HIV-infected patients.
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