Pro- and anti-inflammatory gene expression in the murine small intestine and liver after chronic exposure to alcohol

Background: Endotoxin has been proposed to play a primary role in ALD, by i nitiating an inflammatory cascade within the liver. Although the source of these cytokines has been presumed to be circulating monocytes or tissue mac rophages, 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 hypot hesized that alcohol would alter cytokine expression within the small intes tine of mice exposed to ethanol and that LPS would alter levels of cytokine expression even more dramatically. Methods: 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 alan ine aminotransferase (ALT) and cytokine levels, histology, and RT-PCR of pr o- and anti-inflammatory cytokine gene expression were determined from dist al ileum and liver samples. Translocation of intestinal bacterial flora als o was assessed. Results: Ethanol exposure upregulated basal gene expression of IL-1 beta, T NF-alpha, IL-6, and iNOS in the distal ileum, but similar effects of ethano l on the liver were not observed. In contrast, LPS challenge of ethanol-exp osed mice increased intestinal gene expression of some cytokines, but decre ased 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 molecul es was inhibited in mice that received both ethanol and LPS. Finally, where as basal levels of hepatic IL-11 mRNA were not elevated by exposure to etha nol, intestinal IL-11 mRNA levels were increased more than 100-fold. Conclusions: These studies are the first to show that ethanol affects cytok ine gene expression in the ileum and identifies the ileum as a potential ta rget for ethanol effects. In addition, our results suggest that IL-ll expre ssion 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.