S05
ALCOHOL AND INFLAMMATION
S05.1 THE ROLE OF CYTOKINES IN ALCOHOLIC STEATOHEPATITIS
- H. Tilg1,2
+ Author Affiliations
Abstract
Ethanol treatment increases the production of reactive oxygen species (ROS) and lowers antioxidant levels, thereby enhancing oxidative stress in many tissues. ROS are capable of initiating lipid peroxidation and lead to the release of reactive aldehydes with potent pro-inflammatory and pro-fibrotic properties. Various pro-inflammatory cytokines such as TNFα, IL-1, IL-8 and others have been proposed to play a major role in alcoholic steatohepatitis (ASH). Serum concentrations TNF and of various TNF-inducible cytokines such as IL-1 and IL-8 are increased in patients with acute ASH. Several studies in rats, mice and tissue culture focused on the role of cytokines, especially TNF, in experimental models of alcoholic liver disease. Studies neutralizing other pro-inflammatory cytokines such as IL-1 or IL-8 are currently not available. Furthermore, alcohol-associated liver injury is inhibited when the animals are treated with poorly absorbed oral antibiotics or lactobacillus to decrease endotoxaemia, supporting the hypothesis that gut-derived bacterial products such as endotoxin might be important in activation of Kupffer cells and/or other cell types in the liver. This fits with the observation that chronic ethanol feeding causes more severe liver injury in wild-type mice than in CD14 knockouts. These results further support that gut-derived endotoxin acting via its cellular receptor CD14 plays a major role in the development of alcohol-induced liver injury. In experimental models and isolated hepatocytes, alcohol has been shown to induce liver cell apoptosis. Evidence from rat studies indicates that ethanol-induced gut leakiness and endotoxemia precedes liver inflammation, suggesting that indeed ethanol-induced gut damage come firs. Even though cytokine dysregulations in ASH may constitute secondary phenomena, blockade of these highly pro-inflammatory molecules remains a potential treatment concept.
- © The Author 2011. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
- V. Buko,
- P. Kirvel,
- E. Naruta,
- E. Belanovskaya,
- P. Voronov and
- O. Lukivskaya
+ Author Affiliations
Abstract
The activation of TNFα, the key pro-inflammatory cytokine, plays an important role in alcoholic liver disease. TNFα mediates inflammatory process and accelerates lipid accumulation in the liver under alcoholic steatohepatitis (ASH). Therapy with anti-TNFα antibodies is mainly in use in the clinics for acute alcoholic hepatitis but not for ASH. In the study that we carried out, the monoclonal anti-TNFα antibodies remicade (REM; 1 and 10 mg/kg, i.p) administered during 10 days decreased necrotic foci and lymphocytic infiltration but unaffected steatosis in the liver of rats with ASH induced by feeding of the Lieber-DeCarli ethanol-containing diet (LCD). Only the high dose of REM lowered liver triglyceride content and serum alkaline phosphatase (AP) activity. Both REM doses raised phagocytic index and circulating immune complexes and normalized complement activity. As the treatment of ASH with REM rather benefits inflammatory signs, we used REM in combinations with promising hepatoprotectors to improve steatosis. We administered REM simultaneously with i.g. administration of sesamine (500 mg/kg), pioglytasone (10 mg/kg), betaine (100 mg/kg) or metformine (50 mg/kg). The combinations of REM with betaine and sesamine were more effective than REM alone in decreasing serum AP activity, square of sudanophylic staining and triglyceride content in the liver. All combinations did not disturb immunomodulatory properties of REM. These experimental studies suggest that anti-TNFα antibodies combined with the hepatoprotectors (sesamine, betaine) are effective in necrosis, inflammation and steatosis in the experimental model of ASH induced by LCD feeding.
- K. Pantopoulos
+ Author Affiliations
Abstract
Alcoholic liver disease (ALD) is frequently associated with hepatic iron overload that contributes to liver injury and is considered as a risk factor for the development of liver fibrosis. Dietary iron absorption and body iron traffic are controlled by the iron regulatory hormone hepcidin, a liver-derived peptide that binds to the iron exporter ferroportin and promotes its internalization and degradation. This leads to retention of iron within ferroportin-expressing cells, including duodenal enterocytes, reticuloendothelial macrophages and hepatocytes. The expression of hepcidin is regulated transcriptionally in response to iron, inflammation and stress signals. Experiments in cells and mouse models demonstrated that ethanol suppresses hepcidin mRNA transcription by inhibiting the binding of the constitutive transcription factor C/EBPα within its promoter. Ethanol-dependent downregulation of hepcidin is associated with increased expression of the duodenal iron transporters DMT1 and ferroportin at the apical and basolateral membranes of enterocytes, respectively. These findings provide a framework to understand the molecular mechanisms underlying hepatic iron accumulation in ALD patients. To better characterize the role of iron in chemically induced liver fibrogenesis, hemojuvelin knockout (Hjv − /−) mice, a model of hemochromatosis, and wild-type controls were subjected to intoxication with CCl4. Hjv − /− mice developed earlier and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF. Thus, hepatic iron overload potentiates the effects of chemical intoxication and triggers precocious profibrogenic gene expression. Although the CCl4 model may simulate pathophysiological responses of ALD, further experiments with ethanol intoxication are required to validate these data
- G. Millonig
+ Author Affiliations
Abstract
Hepatitis of any kind is characterized by increased concentrations of reactive oxygen species. H2O2 is the main reactive oxygen intermediate derived from a multitude of cellular metabolic processes as well as from oxidative burst by granulocytes or macrophages. Due to its relatively long half-life time, there is growing evidence that H2O2 also acts as a signaling molecule. Iron metabolism can be influenced by H2O2 by activating the iron regulatory protein 1, which regulates intracellular iron metabolism but also by increasing transferrin receptor 1 that is responsible for cellular iron uptake. Both mechanisms lead to increased cellular iron uptake and decreased levels of circulating serum iron. Hepcidin, the systemic iron regulator, has not been linked to oxidative stress so far. New experiments, however, point out that H2O2 is able to increase hepcidin via STAT3 signaling, thus decreasing iron recycling by macrophages and iron resorption by the duodenum. This is a third mechanism to lower serum iron during increased oxidative stress and preventing toxic reactions between H2O2 and iron.
