Ethanol Inhibits Lipid Raft-Mediated TCR Signaling and IL-2 Expression: Potential Mechanism of Alcohol-Induced Immune Suppression
Ethanol Inhibits Lipid Raft-Mediated TCR Signaling and IL-2 Expression: Potential Mechanism of Alcohol-Induced Immune Suppression
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DOI：
10.1111/j.1530-0277.2011.01479.x
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发表时间：
2011-08-01
影响因子：
3.2
通讯作者：
Joshi-Barve, Swati
中科院分区：
文献类型：
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作者：
Ghare, Smita;Patil, Madhuvanti;Joshi-Barve, Swati
背景：酒精滥用对免疫系统有长期的有害影响，并导致调节天然免疫和获得性免疫的CD4(+)T淋巴细胞的功能衰竭和丧失。通过T细胞受体(TCR)激活T淋巴细胞，涉及到脂筏共定位和蛋白质聚集到免疫信号小体中，从而触发一系列信号级联反应，从而产生白介素2(IL-2)。IL-2调节活化T细胞的增殖和克隆性扩增，对有效的免疫反应是必不可少的。本工作基于乙醇下调脂类RAFT介导的TCR信号转导和产生IL-2的假设，探讨了乙醇诱导的CD4(+)T淋巴细胞功能障碍的机制。方法：将原代或培养的人T淋巴细胞暴露于乙醇中24小时，然后用抗CD3/抗CD28抗体或植物血凝素刺激。结果：原代和培养的人CD4(+)T淋巴细胞暴露于生理浓度的乙醇后，通过抑制IL-2的关键转录因子NFAT的DNA结合活性，导致IL-2mRNA和蛋白表达下调。乙醇降低酪氨酸磷酸化和上游信号蛋白PLC Gamma 1、LAT、ZAP70和Lck的激活。这些影响可以通过抑制乙醇的新陈代谢来防止。蔗糖密度梯度分级和共聚焦显微镜显示，乙醇抑制了必需的上游脂筏介导的TCR依赖的信号事件，即Lck、ZAP70、LAT和PLC Gamma 1与质膜脂筏的共定位。结论：总体上，我们的数据表明乙醇抑制了脂筏介导的CD4(+)T淋巴细胞的TCR信号，从而抑制了IL-2的产生。这些发现可能代表了一种与酗酒相关的免疫抑制的新机制，并可能与艾滋病毒/艾滋病和丙型肝炎病毒感染等疾病特别相关，在这些疾病中，酗酒是已知的共病。
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. The present work examines the mechanisms underlying ethanol-induced dysfunction of CD4(+) T lymphocytes based on the hypothesis that ethanol downregulates lipid raft-mediated TCR signal transduction and resultant IL-2 production.Methods: Primary or cultured human T lymphocytes were exposed to ethanol for 24 hours prior to stimulation with anti-CD3/anti-CD28 antibodies or phytohemagglutinin. Effects of ethanol exposure on TCR-signaling (including activation of Lck, ZAP70, LAT, and PLC gamma 1) and IL-2 gene expression were examined.Results: Exposure of both primary and cultured human CD4(+) T lymphocytes to physiologically relevant concentrations of ethanol leads to down-regulation of IL-2 mRNA and protein via inhibition of DNA-binding activity of NFAT, the essential transcription factor for IL-2. Ethanol decreases tyrosine phosphorylation and activation of upstream signaling proteins PLC gamma 1, LAT, ZAP70, and Lck. These effects are prevented by inhibition of metabolism of ethanol. Sucrose density gradient fractionation and confocal microscopy revealed that ethanol inhibited essential upstream lipid raft-mediated TCR-dependent signaling events, namely colocalization of Lck, ZAP70, LAT, and PLC gamma 1 with plasma membrane lipid rafts.Conclusions: Overall, our data demonstrate that ethanol inhibits lipid raft-mediated TCR-signaling in CD4(+) T lymphocytes, resulting in suppression of IL-2 production. These findings may represent a novel mechanism underlying alcohol abuse-associated immune suppression and may be particularly relevant in diseases such as HIV/AIDS and hepatitis C virus infection where alcohol abuse is a known comorbidity.