The effect of inflammatory cytokines in alcoholic liver disease

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.

Figure 1

The natural history of alcoholic liver disease. Chronic ethanol consumption leads to fatty liver for more than 90%. But only up to 40% of this population develops more severe forms of alcoholic liver disease (ALD), including fibrosis and alcoholic hepatitis. Continuous ethanol consumption finally leads to liver cirrhosis or hepatocellular carcinoma and leads to death.

Figure 2

The pathogenic mechanisms of alcoholic liver disease. Chronic ethanol consumption promotes the translocation of LPS from the intestine to the portal vein, where it binds to the lipopolysaccharide-binding protein (LBP). STATs induces liver regeneration. Ethanol consumption alters the intracellular balance of antioxidants with subsequent decrease in the release of mitochondrial damage, leading to hepatic apoptosis. Hepatocytes and activated Kupffer cells are suggested to be the sources of oxidative stress, which are responsible for lipid peroxidation and further apoptotic damage. Activation of hepatic stellate cells also contributes to the production of TGF-β, ROS, and cytokines, leading to liver fibrosis.

Figure 3

The pathway of ethanol metabolism. Ethanol is metabolized into acetaldehyde by alcohol dehydrogenase (ADH) and the microsomal enzyme cytochrome P450 2E1 (CYP2E1). The ADH enzyme reaction is the main ethanol metabolic pathway involving an intermediate carrier of electrons, namely, nicotinamide adenine dinucleotide (NAD⁺). Acetaldehyde is rapidly metabolized by aldehyde dehydrogenase (ALDH) in the mitochondria to acetate and NADH. And acetate is eventually metabolized in the muscle to carbon dioxide and water.

Figure 4

Toll-like receptor 4 signaling pathway in alcohol consumption. Ethanol promotes the translocation of lipopolysaccharide from the gastrointestinal lumen to the portal vein, where it binds to the lipopolysaccharide-binding protein. In Kupffer cells, lipopolysaccharide binds to CD14, which combines with TLR4 activating multiple cytokine genes. TLR4 are activated by MyD88 dependent or independent manner, leading to secretion of TNF-α or IFN-β.