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.
"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) . Elevated IL-6 is found in chronic alcohol-fed animals and in alcoholics, with or without liver disease . 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   . "
[Show abstract][Hide abstract] ABSTRACT: Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.
Mediators of Inflammation 12/2013; 2013(3):495156. DOI:10.1155/2013/495156 · 3.24 Impact Factor
"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). "
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress has been proposed as one of the mechanisms of alcohol-induced brain shrinkage and alcohol-induced hepatotoxicity. The aim of this study was to assess the correlations between liver function and brain volume (BV) measurements in patients with alcohol dependence.
We recruited 124 patients with alcohol dependence and 111 healthy control subjects from National Institute of Health, National Institute on Alcohol Abuse and Alcoholism inpatient alcohol treatment program. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as hematocrit (Hct) and albumin were assayed shortly after admission. Magnetic resonance imaging examination was conducted in both groups (after 3-week abstinence in the patient group). We used stepwise linear regression analyses to determine the variables most strongly correlated with brain shrinkage.
Patients with alcohol dependence had lower BV, and greater brain shrinkage as measured by gray matter ratio (GMR), white matter ratio (WMR), brain ratio (BR), and higher cerebrospinal fluid ratio ratio (CSFR) compared with their healthy counterparts. Age and sex were significantly correlated with some BV measurements in both patient and control groups. Body mass index (BMI) was significantly correlated with CSFR, BR, GMR, and WMR; Hct with CSFR and BR; serum GGT level with BV, CSFR, BR, GMR, and WMF in the patient group. No biological variables were correlated with BV indices in the control group. In gender-stratified analysis, age was significantly correlated with brain shrinkage in male patients but not in female patients. Serum GGT level in male and female patients, Hct in male patients, and AST levels in female patients were significantly correlated with brain shrinkage.
Our results showed that the higher levels of liver function indices, especially GGT, correlated with BV shrinkage as measured using CSFR, BR, GMR, and WMR in patients with alcohol dependence but not in controls. Serum GGT level outweighed aging effect on brain shrinkage in female patients.
Alcoholism Clinical and Experimental Research 10/2011; 36(4):625-32. DOI:10.1111/j.1530-0277.2011.01662.x · 3.21 Impact Factor
"Aldehyde-protein adducts and hydroxyl radicals can cause liver injury by stimulating intense immune responses directed against the modified proteins, as demonstrated by antibodies detected in sera of chronic alcohol-exposed experimental animals66 and humans.11 Sera of heavy drinkers may contain high titers of IgM, IgG and IgA antibodies to acetaldehyde adducts.67–69 Associated “auto-immune” attacks on hepatocytes cause necrosis,70 and with continued rounds of inflammation, necrosis, oxidative stress, ROS generation, and further adduct formation, fibrosis ensues.71 "
[Show abstract][Hide abstract] ABSTRACT: Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD), with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC). Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2-15%) versus cirrhosis (15-20%) is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular system and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC.
Oxidative Medicine and Cellular Longevity 03/2010; 3(3):178-85. DOI:10.4161/oxim.3.3.12288 · 3.36 Impact Factor
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