Molecular targets in the treatment of alcoholic hepatitis

Figure 1 The effects of alcohol on the innate and adaptive immune system. Alcohol is metabolised by gut microbiota to acetaldehyde which has a direct effect on the epithelial tight junctions, making them more leaky. Endotoxin and other pathogen-associated molecular patterns enter the portal circulation and act via toll-like receptor (TLR) 4 receptors on kupffer cells (KCs) and macrophages (MAC), activating them to produce pro-inflammatory cytokines and chemokines, which act on hepatocytes, neutrophils (NEUT) and T cells. Both CD4⁺ and CD8⁺ T cells are recruited into the liver but there is a significant proportion of interleukin (IL)-17 secreting CD4⁺ Th17 cells, which in turn activate stellate cells to produce IL-8. T cells also act directly on hepatocytes via the tumor necrosis factor (TNF) receptor 1 or Fas pathways leading to apoptosis. Alcohol also has a direct effect on hepatocytes (HEP) through metabolism by alcohol dehydrogenase, the microsomal ethanol-oxidising system and peroxisomal catalase to acetaldehyde, which damages cells by the formation of reactive oxygen species (ROS) and increased lipid peroxidation. HSC: Hepatic stellate cell; MCP: Monocyte chemotactic protein.