Regulation of macrophage activation in alcoholic liver disease

Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor alpha (TNF alpha). The regulation of TNF alpha synthesis is controlled by both transcriptional and post-transcriptional mechanisms via the integration of complex signal transduction pathways activated in response to LPS exposure. Recent data has shown that increased LPS-stimulated phosphorylation of extracellular signal-regulated kinase pathway 1/2 (ERK1/2) is one of the important molecular targets of chronic ethanol in Kupffer cells. This increased activation of ERK1/2 after chronic ethanol is associated with increased expression of Egr-1, a transcription factor required for enhanced LPS-stimulated TNF alpha mRNA expression after chronic ethanol exposure. egr-1 null mice are protected from the development of fatty liver injury in response to chronic ethanol feeding, identifying an essential role for Egr-1 in the development of chronic ethanol-induced liver injury. Here we review recent studies aimed at understanding the mechanisms by which chronic ethanol enhances the LPS -> ERK1/2 -> Egr-1 ->Tau NF alpha pathway in Kupffer cells. These studies identify a critical role for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species in the activation of ERK1/2 and subsequent production of TNF alpha in Kupffer cells after chronic ethanol feeding.