Fleming S, Toratani S, Shea-Donohue T, Kashiwabara Y, Vogel S N, Metcalf E S
Department of Microbiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Alcohol Clin Exp Res. 2001 Apr;25(4):579-89.
Endotoxin has been proposed to play a primary role in ALD, by initiating an inflammatory cascade within the liver. Although the source of these cytokines has been presumed to be circulating monocytes or tissue macrophages, ethanol-induced, nonhepatic sources of soluble mediators recently have been identified. One potential, but not clearly defined, extrahepatic source of cytokines in ALD is the intestine. In the current study, we hypothesized that alcohol would alter cytokine expression within the small intestine of mice exposed to ethanol and that LPS would alter levels of cytokine expression even more dramatically.
Mice were fed a modified Lieber-DeCarli liquid ethanol or control diet for up to 14 days prior to injecting either saline or LPS. Plasma alanine aminotransferase (ALT) and cytokine levels, histology, and RT-PCR of pro- and anti-inflammatory cytokine gene expression were determined from distal ileum and liver samples. Translocation of intestinal bacterial flora also was assessed.
Ethanol exposure upregulated basal gene expression of IL-1 beta, TNF-alpha, IL-6, and iNOS in the distal ileum, but similar effects of ethanol on the liver were not observed. In contrast, LPS challenge of ethanol-exposed mice increased intestinal gene expression of some cytokines, but decreased expression of others. These effects were not associated with bacterial translocation. Also, ethanol alone induced a modest increase in both ICAM-1 and TLR4 mRNA expression in the intestine, but expression of both molecules was inhibited in mice that received both ethanol and LPS. Finally, whereas basal levels of hepatic IL-11 mRNA were not elevated by exposure to ethanol, intestinal IL-11 mRNA levels were increased more than 100-fold.
These studies are the first to show that ethanol affects cytokine gene expression in the ileum and identifies the ileum as a potential target for ethanol effects. In addition, our results suggest that IL-11 expression may be enhanced in the intestine to help repair or protect this organ from alcohol-induced damage. Collectively, these studies suggest that both pro- and anti-inflammatory soluble mediators in the intestine maintain and exacerbate the local hepatic response to ethanol.
内毒素被认为通过启动肝脏内的炎症级联反应在酒精性肝病（ALD）中起主要作用。尽管这些细胞因子的来源被推测为循环单核细胞或组织巨噬细胞，但最近已确定乙醇诱导的非肝脏可溶性介质来源。ALD中细胞因子的一个潜在但尚未明确界定的肝外来源是肠道。在本研究中，我们假设酒精会改变暴露于乙醇的小鼠小肠内细胞因子的表达，并且脂多糖（LPS）会更显著地改变细胞因子的表达水平。
在注射生理盐水或LPS之前，给小鼠喂食改良的Lieber-DeCarli液体乙醇或对照饮食长达14天。从回肠末端和肝脏样本中测定血浆丙氨酸转氨酶（ALT）和细胞因子水平、组织学以及促炎和抗炎细胞因子基因表达的逆转录聚合酶链反应（RT-PCR）。还评估了肠道细菌菌群的易位情况。
乙醇暴露上调了回肠末端IL-1β、肿瘤坏死因子-α（TNF-α）、IL-6和诱导型一氧化氮合酶（iNOS）的基础基因表达，但未观察到乙醇对肝脏有类似影响。相比之下，对暴露于乙醇的小鼠进行LPS刺激会增加一些细胞因子的肠道基因表达，但会降低其他细胞因子的表达。这些影响与细菌易位无关。此外，单独乙醇会诱导肠道中细胞间黏附分子-1（ICAM-1）和Toll样受体4（TLR4）mRNA表达适度增加，但在同时接受乙醇和LPS的小鼠中，这两种分子的表达均受到抑制。最后，虽然暴露于乙醇不会提高肝脏IL-11 mRNA的基础水平，但肠道IL-11 mRNA水平增加了100多倍。
这些研究首次表明乙醇会影响回肠中的细胞因子基因表达，并确定回肠是乙醇作用的潜在靶点。此外，我们的结果表明肠道中IL-11的表达可能会增强，以帮助修复或保护该器官免受酒精诱导的损伤。总体而言，这些研究表明肠道中的促炎和抗炎可溶性介质维持并加剧了肝脏对乙醇的局部反应。
