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Keywords:

  • alcoholic liver disease;
  • extracellular signal-regulated kinase pathway 1/2;
  • Kupffer cells;
  • lipopolysaccharide;
  • nicotinamide adenine dinucleotide phosphate (NADPH) oxidase

Abstract

Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor α (TNFα). The regulation of TNFα 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 TNFα 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[RIGHTWARDS ARROW]ERK1/2[RIGHTWARDS ARROW]Egr-1[RIGHTWARDS ARROW]ΤNFα 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 TNFα in Kupffer cells after chronic ethanol feeding.