title: 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 impairment of multiple immune functions. Our work has shown that ethanol can sensitize CD4(+) T lymphocytes to caspase-3-dependent activation-induced cell death (AICD). It has been demonstrated that the formation of S-adenosylmethionine (SAMe) catalyzed by methionine adenosyltransferase (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 (25 mM) 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. Furthermore, 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 show that MAT II and SAMe are critical molecular components essential for CD4(+) T-cell survival that are affected by ethanol, leading to enhanced AICD. Furthermore, these studies provide a clinical paradigm for the development of much needed therapy using SAMe supplementation in the treatment of immune dysfunction induced by alcohol abuse.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA.
authors.forename: Prachi T
authors.initials: PT
authors.lastname: Hote
authors.forename: Rashmita
authors.initials: R
authors.lastname: Sahoo
authors.forename: Tanvi S
authors.initials: TS
authors.lastname: Jani
authors.forename: Smita S
authors.initials: SS
authors.lastname: Ghare
authors.forename: Theresa
authors.initials: T
authors.lastname: Chen
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi-Barve
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Shirish S
authors.initials: SS
authors.lastname: Barve
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D019169:Jurkat Cells; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D000431:Ethanol; D012436:S-Adenosylmethionine; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D053148:Caspase 3