Ethanol inhibits lipid raft-mediated TCR signaling and IL-2 expression: potential mechanism of alcohol-induced immune suppression.

Background: Alcohol abuse has long-term deleterious effects on the immune system, and results in a depletion and loss of function of CD4(+) T lymphocytes, which regulate both innate and adaptive immunity. T-lymphocyte activation via T-cell receptor (TCR) involves the lipid raft colocalization and aggregation of proteins into the immunological signalosome, which triggers a signaling cascade resulting in the production of interleukin-2 (IL-2). IL-2 regulates the proliferation and clonal expansion of activated T cells and is essential for an effective immune response.

Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells.

Methionine adenosyltransferase II (MAT II) is a key enzyme in cellular metabolism and catalyzes the formation of S-adenosylmethionine (SAMe) from L-methionine and ATP. Normal resting T lymphocytes have minimal MAT II activity, whereas activated proliferating T lymphocytes and transformed T leukemic cells show significantly enhanced MAT II activity. This work was carried out to examine the role of MAT II activity and SAMe biosynthesis in the survival of leukemic T cells.

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.

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.

Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes.

Unlabelled: Obesity and the metabolic syndrome are closely correlated with hepatic steatosis. Simple hepatic steatosis in nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), which can be a precursor to more serious liver diseases, such as cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms underlying progression of steatosis to NASH remain unclear; however, inflammation, proinflammatory cytokines, and oxidative stress have been postulated to play key roles.

Interactions of cytokines, S-Adenosylmethionine, and S-Adenosylhomocysteine in alcohol-induced liver disease and immune suppression.

Alcoholic liver disease (ALD) remains a leading cause of death in the USA. Defining mechanisms for liver cell death in ALD in order to develop potential new agents for therapeutic intervention is a major focus of the authors' work. Abnormal cytokine metabolism is a major feature of ALD, and a thorough understanding of both mechanisms and interactions of cytokine overproduction and sensitization are critical to developing a possible treatment for ALD.