Immune Responses to Ethanol Metabolites and Cytokine Profiles Differentiate Alcoholics with or without Liver Disease.

Department of Laboratory Medicine and Addiction Research Unit, EP Central Hospital, Seinäjoki, and University of Tampere, Finland.
The American Journal of Gastroenterology (Impact Factor: 9.21). 07/2005; 100(6):1303-10. DOI: 10.1111/j.1572-0241.2005.41509.x
Source: PubMed

ABSTRACT Excessive alcohol consumption is associated with the generation of antibodies against neoantigens induced by ethanol metabolism. However, the associations between such immune responses, ethanol consumption, and liver injury remain unclear.
Eight-six male alcoholics with (n=54) or without (n=32) liver disease, and 20 male volunteers (6 abstainers, 14 moderate drinkers) underwent clinical, morphological, and biochemical assessments of liver status and ethanol consumption.
Antiacetaldehyde adduct IgAs in both groups of alcoholics were significantly higher than those in the controls. Elevated IgGs occurred in patients with liver disease, whereas IgMs were high in the heavy drinkers without apparent liver disease. Liver disease patients had high levels of both proinflammatory (IL-2, IL-6, IL-8, TNF-alpha) and antiinflammatory (IL-10) cytokines, whereas those without liver disease showed elevated IL-6, IL-8, and IL-10 only. Ethanol consumption correlated significantly with antiadduct IgA and IL-6 levels, which also showed parallel changes upon abstinence.
Alcoholic liver disease is associated with the generation of IgAs and IgGs against acetaldehyde-derived antigens and enhanced levels of both pro- and antiinflammatory cytokines, whereas elevated IgA, IL-6, and IL-10 characterize alcoholics without liver disease. These data suggest that immunological mechanisms may play a role in the sequence of events leading to liver disease in some patients with excessive drinking.

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    • "IL-6 and IL-10 are two cytokines that play roles in reducing alcoholic liver injury and inflammation through activation of the signal transducer and activator of transcription (STAT3) [12]. Elevated IL-6 is found in chronic alcohol-fed animals and in alcoholics, with or without liver disease [32]. On the other hand, IL-6 knockout mice fed chronic alcohol showed increased liver fat accumulation, lipid peroxidation, mitochondrial DNA damage, and sensitization of hepatocytes to TNF-í µí»¼ induced apoptosis, which was prevented by the administration of recombinant IL-6 [31] [33] [34]. "
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    • "In animal studies, alcohol induced Kupffer cell to produce tumor necrosis factor-alpha (TNF-alpha) (Kono et al., 2000; Zhou et al., 2003). Elevated TNF-alpha has been reported in patients with alcohol dependence, especially those with alcohol-induced liver disease (Latvala et al., 2005), and is correlated with liver function impairment (Gonzalez-Quintela et al., 2008). Systemic TNF-alpha in patients with alcohol dependence can be transported from serum to the brain (Banks, 2005) and activate inflammatory responses (Qin et al., 2007). "
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    • "On the other hand, CYP2E1 inhibition has been reported to inhibit both ethanol-induced alterations in cytokine expression and liver pathology (Morimoto et al., 1995; Albano et al., 1996; Fang et al. 1998; Gouilon et al., 2000). Over expression of ADH also results in hepatocyte toxicity and acetaldehyde both inhibits hepatocyte proliferation (Lieber, 2004; Clemens, 2007) and generates protein adducts (Latavala et al., 2005). "
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