The Response of Liver Macrophages to Inflammatory Stimulation

The gut is the major source of inflammatory agents that affect the liver. Of these com-pounds, the endotoxins are the most frequent and best studied intruders. The resident macrophages of the liver, the Kupffer cells, are among the first to respond to this complex. Following contact with the cluster of differentiation (CD) 14 protein, the complex triggers a signal cascade involving the nuclear factor KB. This factor enhances the expression of inflammation-related genes, e.g. those encoding cytokines. Tumor necrosis factor-a is responsible for nearly all of the effects ascribed to endotoxins (lipopolysaccharides). Interleukin (IL)-6, also a product of lipopolysaccharide-activated Kupffer cells, may be instrumental in eliciting the acute-phase response of hepatocytes, while transforming growth factor-β promotes conversion of quiescent hepatic stellate cells into a collagen-producing myofibroblast-like form. A different signal pathway triggered by bound endotoxin involves a mitogen-activated protein kinase and leads to the activation of phospholipase A2 and the synthesis of the eico-sanoids. Endotoxin also induces a nitric oxide synthase in Kupffer cells. This inorganic mediator may participate in the relaxation of the hepatic sinusoid, but may also, together with macrophage-derived superoxide, produce strong oxidants. Tumor necrosis factor-a and nitric oxide play a significant role during liver regeneration after partial hepatectomy. Of the various effects of eicosanoids, their regu-latory role in cytokine production by Kupffer cells may be the most important. The regulation of Kupffer cell functions by cell volume change has very recently become apparent.