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Ethanol Inhibits Lipid Raft‐Dependent TCR Signaling and IL‐2 Expression: Potential Mechanism of Alcohol‐Induced Immune Suppression
Author(s) -
JoshiBarve Swati,
Ghare Smita,
Patil Madhuvanti,
Hote Prachi,
Suttles Jill,
McClain Craig,
Barve Shirish
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.966.9
Subject(s) - lipid raft , t cell receptor , nfat , immune system , microbiology and biotechnology , biology , t cell , signal transduction , acquired immune system , innate immune system , immunology , chemistry , transcription factor , biochemistry , gene
Alcohol abuse has long‐term deleterious effects on the immune system, and results in reduced function of CD4+T lymphocytes, which regulate both innate and adaptive immunity. T lymphocyte activation via T‐cell receptor (TCR) involves the plasma membrane lipid raft‐dependent aggregation of proteins into the immunological signalosome, which in turn, triggers a signaling cascade resulting in interleukin‐2 (IL‐2) production. IL‐2 is a critical cytokine that regulates the proliferation/clonal expansion of activated T‐cells, and is essential for an effective immune response. The present work examines the mechanisms underlying ethanol‐induced dysfunction of CD4+T lymphocytes, and demonstrates for the first time, that physiologically relevant concentrations of ethanol inhibit lipid raft‐dependent TCR signaling and decrease production of IL‐2 in both primary and cultured human CD4+T lymphocytes. Specifically, ethanol substantially down‐regulates lipid raft colocalization and activation/phosphorylation of Lck, ZAP70 and LAT, resulting in a marked decrease in DNA‐binding activity of NFAT and IL‐2 mRNA and protein. Importantly, inhibition of ethanol metabolism prevented these inhibitory effects. Overall, our findings have clinical relevance in alcohol abuse‐associated immune dysfunction, especially in conditions such as HIV and HCV infection where alcohol abuse is a known comorbidity.