Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression

Abstract

An important aspect in alcohol abuse associated immune suppression is the loss of T helper CD4 + lymphocytes leading to an impairment of multiple immune functions. Our work has shown that ethanol can sensitize CD4 + T lymphocytes to activation-induced, caspase-3 dependent cell death (AICD). It has been demonstrated that formation of S-adenosylmethionine (SAMe) catalyzed by methionine adenosyltransferase II (MAT II) is essential for CD4 + T cell activation and proliferation. Since ethanol is known to affect SAMe metabolism in hepatocytes, we investigated the effect of ethanol on MAT II activity/expression, SAMe biosynthesis and cell survival in CD4 + T lymphocytes. We demonstrate for the first time that ethanol at a physiologically relevant concentration (25mM) substantially decreased the enzymatic activity of MAT II in T lymphocytes. Ethanol was observed to decrease the transcription of MAT2A, which encodes the catalytic subunit of MAT II and is vital for MAT II activity and SAMe biosynthesis. Further, correspondent to its effect on MAT II, ethanol decreased intracellular SAMe levels and enhanced caspase-3 dependent AICD. Importantly, restoration of intracellular SAMe levels by exogenous SAMe supplementation considerably decreased both caspase-3 activity and apoptotic death in T lymphocytes. In conclusion, our data shows that MAT II and SAMe are critical molecular components essential for CD4 + T cell survival which are affected by ethanol leading to enhanced Address correspondence to: Shirish Barve PhD, Professor, Department of Medicine, Pharmacology and Toxicology, University of Louisville Medical Center, 511 S. Floyd, MDR Bldg., Rm#526, Louisville, KY 40202. Tel. 502 852 -5245; Fax. 502 562 -4271; shirish.barve@louisville.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AICD. Furthermore, these studies provide a clinical paradigm for the development of the much needed therapy using SAMe supplementation in the treatment of immune dysfunction induced by alcohol abuse. HHS Public Access

Creatine Supplementation Does Not Prevent the Development of Alcoholic Steatosis

“…Furthermore, it is reasonable to suppose that while EtOH and high‐fat or choline deficiency diets all affect the methionine metabolic pathway, there may be salient differences between which enzymes are being affected by these diets and hence responses to creatine supplementation. However, such comparisons are difficult to do at this time because such detailed analyses on the effects on the methionine metabolism as performed for EtOH exposure by us and others (Hote et al., ; Ji et al., ; Jung et al., ; Kharbanda, , ; Kharbanda and Barak, ; Kharbanda et al., ; Lu et al., ; Villanueva and Halsted, ) have not been performed for these other liver injury models.…”

“…This lowering of the hepatocellular SAM:SAH ratio is primarily because of the EtOH‐induced reduction in the level and activity of methionine synthase, an enzyme of the methionine metabolic pathway that remethylates homocysteine (and thus remove SAH) to generate methionine, the precursor for SAM (Kharbanda and Barak, ). Furthermore, EtOH administration has also been reported to decrease the transcript level and activity of methionine adenosyltransferase (an enzyme that catalyzes the generation of SAM) and reduce the expression of SAH hydrolase, the enzyme responsible for the reversible hydration of SAH into adenosine and homocysteine (Hote et al., ; Lu et al., ; Villanueva and Halsted, ). Hence, we feel it is primarily the EtOH‐induced changes in the expression and activities of the enzymes which regulate SAM and SAH levels, rather than GAMT‐catalyzed reactions that impose a considerable metabolic burden on methyl group metabolism.…”

S-adenosylmethionine in Liver Health, Injury, and Cancer

“…This was thought to be necessary to provide a source of polyamine biosynthesis, and if AdoMet accumulation is prevented, lymphocyte activation was inhibited (57). More recently, Barve and colleagues (95) found that ethanol inhibited MAT2A transcription to result in lower MAT II activity and AdoMet level in T lymphocytes. This sensitized the CD4 + T lymphocytes to caspase-3-dependent activation-induced cell death and may be one of the explanations for alcohol-induced immune suppression (95).…”

“…More recently, Barve and colleagues (95) found that ethanol inhibited MAT2A transcription to result in lower MAT II activity and AdoMet level in T lymphocytes. This sensitized the CD4 + T lymphocytes to caspase-3-dependent activation-induced cell death and may be one of the explanations for alcohol-induced immune suppression (95). The same group of investigators also found that proliferating and transformed T leukemic cells express higher MAT II activity, and inhibiting MAT II expression in these cells resulted in higher caspase-8-dependent apoptosis (101).…”

Coordinated Histone H3 Methylation and Acetylation Regulate Physiologic and Pathologic Fas Ligand Gene Expression in Human CD4+ T Cells

“…Notably, elevated serum levels of soluble FasL and Fas that correlate with the decline in CD4+ T cells are observed in individuals with a history of alcohol abuse (15). Our earlier work has shown that in vitro exposure of human CD4+ T cells to physiologically relevant concentrations of ethanol increases their susceptibility to Fas-and activation-induced apoptotic death (16, 17). Hence, elucidating the mechanisms that govern FasL expression in normal as well as alcohol exposed CD4+ T cells is highly relevant in understanding the regulation of AICD and overall immune responses under both normal and pathologic conditions.…”