Chronic alcohol-induced liver disease inhibits dendritic cell function.

Alcohol-induced disorders have become a serious health problem in USA. About 7.1% of Americans older than 18 years meet the criteria for alcohol abuse (1). All cell types within the liver including hepatocytes, immune cells and hepatic stellate cells may be adversely influenced by ethanol because it affects metabolic, immunological and inflammatory cellular processes. Ethanol consumption is closely related to the progression of HCV infection. Excessive ethanol intake increases HCV RNA levels in serum, which is accompanied by impairment of cellular immunity (2, 3). Heavy ethanol abuse greatly exacerbates the risk of cirrhosis among patients with persistent HCV infection (3, 4). The increased risk of HCV progression in alcoholic patients may be attributed to impaired cellular immunity to viral infection induced by chronic ethanol abuse (2). Long-term ethanol ingestion may broadly influence immunity (5, 6). Previous experimental studies suggest that CD4+ T cell proliferation and cytotoxic T-lymphocyte (CTL) activity responses to NS5 or hepatitis C virus (HCV) core proteins were suppressed by chronic ethanol consumption (3, 7, 8). Further investigations reveal that viral antigen specific impairment of CD4+ T cell proliferation and CTL activity may be restored by interleukin (IL)-2 and granulocyte-macrophage colony-stimulating factor additions (7, 8). These findings imply the potential involvement of antigen presenting cells or dendritic cell (DC) dysfunction in altering the host cellular immune response induced by ethanol. The influence of chronic ethanol exposure on DC function was further explored using a murine model (9). DCs derived from mice fed ethanol for 8-weeks exhibited decreased maturation marker expression such as CD40 and CD80 necessary for antigen presentation although endocytic uptake of proteins exhibited by immature DCs was not affected. Further studies confirmed that allostimulatory activity of DCs derived from ethanol-fed mice was impaired compared with cells isolated from isocaloric pair-fed control animals. Ethanol feeding was shown to suppress pro-inflammatory cytokine [tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-12 and IL-6] production and secretion by DCs when stimulated with lipopolysaccharide (LPS) or poly I:C; in contrast, IL-10 levels were increased. More importantly, impaired CTL responses to HCV NS5 protein observed in ethanol-fed mice could be restored by syngeneic transfer of DCs derived from isocaloric pair-fed controls but not ethanol-fed animals (9). The results from this murine model establish the inhibitory effects of ethanol on DC function and illustrates how it impairs anti-viral immune response (9–13). Similar inhibitory actions of ethanol on human DCs have been observed by others (14–16). However, it is unknown whether the alteration of DC function is due entirely to ethanol alone (without liver disease) or ethanol plus alcoholic liver disease (ALD) using this murine model because there was lack of progressive hepatocyte injury, oxidative stress, mitochondrial dysfunction, severe steatosis and fibrosis upon continued alcohol abuse. Recently, it was observed, unexpectedly, that an outbred Long–Evans (LE) rat strain exhibited many of the pathological, biochemical and molecular features of ethanol-induced hepatotoxicity similar to human disease while on the Lieber–DeCarli liquid diet, which have not been previously observed in any other rodent model (17–20). In this context, we compared the features of ethanol-induced liver injury in the susceptible LE rats with two other inbred strains i.e., Fischer and Sprague–Dawley (18–21); other than mild steatosis, Fischer rats did not develop liver disease whereas Sprague–Dawley had an intermediate phenotype. We hypothesized that DC function may be differentially affected by ALD which could be ideally studied in experimentally susceptible and resistant rat strains. To test this idea, we fed both the LE (sensitive) and Fischer (resistant) rats with the Lieber–DeCarli liquid diet for 8 weeks and compared results to the isocaloric pair-fed controls with respect to the characteristics and downstream effects of ethanol on ALD and DC function because DCs are a critical cellular component in generating robust adaptive immune responses to viral and bacterial pathogens to which alcoholics are highly susceptible. Finally, to determine if alterations in DC functions were directly related to ALD and not to necroinflammatory liver diseae per se, we utilized a liver disease control produced in LE rats. In this model, liver injury was induced in LE rats by treatment with thioacetamide, which has been previously shown to produce severe acute and chronic hepatocyte injury followed by the development of cirrhosis (22, 23).