Alcohol hepatotoxicity: Kupffer cells surface to the top

摘要

In this issue of the Archives of Toxicology, Arthur I. Cederbaum from New York Mount Sinai School of Medicine gives a review on cytokine-mediated hepatotoxicity including a state-of-the-art discussion of the involved signalling pathways (An et al. 2012). A key mechanism of alcoholic liver disease is that ethanol consumption increases levels of gut-derived endotoxins to the portal circulation. As a consequence, Kupffer cells are activated through Toll-like receptors, particularly Toll-like receptor 4 (TLR-4). A well-known consequence of TLR-4-mediated activation of Kupffer cells is secretion of tumour necrosis factor alpha (TNF-alpha), which mediates inflammation and apoptosis. TNF-alpha signals through two receptors, TNF-alpha-R1 and TNF-alpha-R2, which are expressed at higher levels on the hepatocyte membranes compared to all other (non-paren-chymal) liver cell types. Therefore, TNF-alpha is a prototypical cytokine of the Kupffer cell-hepatocyte axis. Cederbaum discusses a number of further mechanisms relevant to alcoholic liver disease, including IL-8 and IL-18, the protective role of adiponectin, AMP-activated protein kinase and transcription factors regulating lipid synthesis, such as SREBPS and sirtuin 1.