Signalling pathways in alcohol-induced liver inflammation

Cells involved in alcoholic liver injury. Alcohol-mediated increase in gut-derived endotoxin with oxidative stress mechanisms sensitizes hepatic macrophages to release inflammatory cytokines such as TNFα, IL-1β, IL-1α and IL-6 that affects stellate cells and hepatocyte functions. Endotoxin also affects stellate cell and endothelial cell activation and contributes to liver injury.

TLR4 mediated signalling in alcohol-exposed macrophages. Alcohol alters functions of Toll-like receptors TLR4 in the liver resulting in regulation of MyD88 dependent activation of downstream signalling molecules such as IRAK kinase, IKK and NFκB. MyD88-independent, TRIF-dependent activation of IRF3 is also regulated alcohol exposure. Alcohol also induces NADPH oxidase via reactive oxygen species leading to inflammation.

TLR4 mediated alcohol-exposed macrophages signalling in alcohol-exposed macrophages. Alcohol alters functions of Toll-like receptors TLR4 in the liver resulting in activation of MAP kinases culminating in alteration of binding to transcription factors such as Egr-1, AP-1 and STAT1. Alcohol also affects cytokine mRNA stability via modulation of MAP kinase activity.