Dai Qun, Pruett Stephen B
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
J Immunotoxicol. 2006 Dec 1;3(4):217-25. doi: 10.1080/15476910601080156.
Both binge and chronic heavy drinking can adversely affect the immune system, but the effects seem to be at least partly dependent on the manner of ethanol (EtOH) consumption. Previous study results from several labs have clearly demonstrated that acute administration of EtOH interferes with innate immune responses. Specifically, EtOH has a general inhibitory effect on cytokine and chemokine production induced by various Toll-like receptor (TLR) ligands, and it suppresses signaling on several levels along the TLR signaling pathways. However, it is not clear whether chronic exposure to ethanol has the same effects or not. The purpose of this study was to investigate the difference between the effect of chronic versus acute EtOH exposure on LPS-induced cytokine production and clustering of components of the TLR4 complex, which is an important early signaling event. Some groups of mice received acute EtOH by oral gavage using our binge drinking model and/or chronic administration of EtOH at 20% (w/v) in the drinking water as the sole liquid source for 4 wk. The cellular distribution of CD14 and TLR4 were studied by confocal microscopy following exposure of peritoneal cells to LPS locally in vivo, and cytokine production in peritoneal fluid and serum was measured by ELISA after LPS injection via a tail vein. Chronic EtOH exposure did not consistently cause significant changes in LPS-induced cytokine production. However, mice previously exposed to chronic EtOH treatment became partially resistant to the suppressive effects of acute EtOH administration with regard to cytokine production. As we have reported previously, acute EtOH treatment suppressed the LPS-induced clustering of TLR4 and CD14 in peritoneal macrophages. However, peritoneal cells from mice treated with chronic EtOH exhibited a greater amount of intracellular expression of CD14 instead of CD14/TLR4 clustering on the membrane following LPS exposure. The results demonstrate different effects of chronic versus acute EtOH treatment on LPS-induced cytokine production in mice. Partial tolerance to the effect of acute EtOH administration caused by chronic EtOH treatment suggests a compensatory mechanism is induced by chronic EtOH administration. Acute EtOH exposure acts probably by disrupting the receptor clustering following LPS recognition, whereas adaptations induced by chronic EtOH treatment seem to involve alteration of LPS receptor expression.
暴饮暴食和长期大量饮酒都会对免疫系统产生不利影响，但这些影响似乎至少部分取决于乙醇（EtOH）的摄入方式。几个实验室先前的研究结果清楚地表明，急性给予EtOH会干扰先天免疫反应。具体而言，EtOH对各种Toll样受体（TLR）配体诱导的细胞因子和趋化因子产生具有普遍抑制作用，并且它在TLR信号通路的多个水平上抑制信号传导。然而，尚不清楚长期接触乙醇是否具有相同的效果。本研究的目的是调查长期与急性EtOH暴露对LPS诱导的细胞因子产生以及TLR4复合物成分聚集的影响之间的差异，TLR4复合物成分聚集是一个重要的早期信号事件。一些小鼠组使用我们的暴饮模型通过口服灌胃接受急性EtOH和/或在饮用水中以20%（w/v）的浓度将EtOH作为唯一液体来源进行4周的长期给药。在体内局部将腹膜细胞暴露于LPS后，通过共聚焦显微镜研究CD14和TLR4的细胞分布，并在通过尾静脉注射LPS后通过ELISA测量腹膜液和血清中的细胞因子产生。长期EtOH暴露并未始终如一地导致LPS诱导的细胞因子产生发生显著变化。然而，先前接受长期EtOH治疗的小鼠在细胞因子产生方面对急性EtOH给药的抑制作用产生了部分抗性。正如我们之前报道的，急性EtOH治疗抑制了LPS诱导的腹膜巨噬细胞中TLR4和CD14的聚集。然而，长期接受EtOH治疗的小鼠的腹膜细胞在LPS暴露后，细胞内CD14的表达量增加，而不是在膜上出现CD14/TLR4聚集。结果表明，长期与急性EtOH治疗对小鼠LPS诱导的细胞因子产生具有不同的影响。长期EtOH治疗引起的对急性EtOH给药效果的部分耐受性表明，长期EtOH给药诱导了一种补偿机制。急性EtOH暴露可能通过破坏LPS识别后的受体聚集起作用，而长期EtOH治疗诱导的适应性变化似乎涉及LPS受体表达的改变。
