TNF signaling

Tumor necrosis factor (TNF)-α is a pleiotropic cytokine involved in the regulation of a wide spectrum of cellular functions including proliferation, inflammation, cell death, and immunity. TNF is the best studied member of the TNF superfamily. In the liver, TNF mediates a wide spectrum of autocrine and paracrine effects that involve liver injury, inflammation, cell death, hepatocellular proliferation, and energy metabolism. Critical to our understanding of TNF function has been the delineation of the complex signaling pathways induced by this factor. Depending on the cellular context and stimulus, TNF can promote either cell proliferation or death. Cell death from TNF can result from either apoptosis or necrosis and these death signaling pathways interact to facilitate cellular destruction. With our increased understanding of TNF signaling pathways has come a realization of the degree of complexity of TNF's effects. Despite the availability of anti-TNF therapies, these agents have not yet proven useful in the treatment of hepatic disease, in large part due to the varied functions exerted by TNF in the liver. This chapter will focus initially on the signaling events that follow TNF ligand-receptor interaction, and subsequently on the functions of TNF signaling in specific pathophysiological states in the liver.