Ishikawa Fumio, Kuwabara Taku, Tanaka Yuriko, Okada Yayoi, Imai Tsunehiko, Momose Yasunori, Kakiuchi Terutaka, Kondo Motonari
Department of Immunology, Toho University School of Medicine, 5-21-16 Ohmori-nishi, Ohta-ku, Tokyo 143-8540, Japan.
Nihon Arukoru Yakubutsu Igakkai Zasshi. 2011 Jun;46(3):319-36.
Alcohol consumption impairs Th1-mediated cellular immune responses and enhances serum IgE levels. It has been reported that the elevated IgE levels are associated with a Th2 polarization response, but the mechanisms for enhancing Th2 polarization by the ethanol treatment remain to be elucidated. The aim of this review is to present and discuss the mechanism of Th2 polarization response by alcohol. IL-12 production by APCs such as monocytes, macrophages, and dendritic cells (DCs) preferentially leads to Th1 polarization. Acute ethanol consumption results in a significant decrease in IL-12 production in LPS-stimulated DCs and a CD40/CD40L interaction between CD40 on the DCs and CD40 ligand expressed on activated T cells. This suggests that Th2 polarization by ethanol is caused by impaired IL-12 production from APCs. In contrast, the induction of IL-10 by LPS is enhanced by ethanol treatment, suggesting that elevated IL-10 may play a role in ethanol-induced suppression of IL-12. However, ethanol inhibited IL-12 production in LPS-stimulated DCs devoid of IL-10 (IL-10/DC), suggesting that down-regulation of IL-12 by ethanol is independent of the IL-10 levels. Furthermore, several studies report that PGE2, cAMP and linolic acid, and endogenous lipid mediators released in inflammatory conditions, also inhibit IL-12 production. These inhibitory effects are similar to the IL-12 inhibition by ethanol. In addition, increase in the levels of these lipid mediators is induced by ethanol treatment. Alternatively, cytokine signaling studies indicate that IL-12 production by DCs is negatively regulated by PI3K and GSK-3, but positively regulated by p38 MAPK, mTOR, and NF-kappa B. Thus, it seems possible that ethanol may interact on the upstream of IL-12 producing a signal pathway. In fact, ethanol alters the stability of cell membrane, and suppresses clustering of TLR4 and recruitment of signaling molecules into lipid rafts, where it associates with the Ser/Thr kinase and the adaptor proteins, and forms a signaling complex. Down-regulation of lipid raft signaling is results in the impaired IL-12 production leading to the Th1 polarization, and causes CD4+ T cells to differentiation toward the Th2 lineage.
饮酒会损害Th1介导的细胞免疫反应并提高血清IgE水平。据报道，升高的IgE水平与Th2极化反应有关，但乙醇处理增强Th2极化的机制仍有待阐明。本综述的目的是介绍和讨论酒精引起Th2极化反应的机制。诸如单核细胞、巨噬细胞和树突状细胞（DC）等抗原呈递细胞（APC）产生的IL-12优先导致Th1极化。急性饮酒会导致LPS刺激的DC中IL-12产生显著减少，以及DC上的CD40与活化T细胞上表达的CD40配体之间的CD40/CD40L相互作用。这表明乙醇引起的Th2极化是由APC产生IL-12受损所致。相反，乙醇处理会增强LPS诱导的IL-10产生，提示升高的IL-10可能在乙醇诱导的IL-12抑制中起作用。然而，乙醇在缺乏IL-10的LPS刺激的DC（IL-10/DC）中抑制IL-12产生，表明乙醇对IL-12的下调与IL-10水平无关。此外，多项研究报告称，PGE2、cAMP和亚油酸以及炎症条件下释放的内源性脂质介质也会抑制IL-12产生。这些抑制作用与乙醇对IL-12的抑制作用相似。此外，乙醇处理会诱导这些脂质介质水平升高。另外，细胞因子信号研究表明，DC产生的IL-12受PI3K和GSK-3负调控，但受p38 MAPK、mTOR和NF-κB正调控。因此，乙醇似乎有可能在产生信号通路的IL-12上游相互作用。事实上，乙醇会改变细胞膜的稳定性，并抑制TLR4的聚集以及信号分子募集到脂筏中，在脂筏中它与Ser/Thr激酶和衔接蛋白结合，并形成信号复合物。脂筏信号的下调导致IL-12产生受损，从而导致Th1极化，并使CD4+T细胞向Th2谱系分化。
