Tumor necrosis factor-α (TNF) is a pleiotropic cyto-kine whose biological functions regulate the cellular responses of injury and repair, inflammation and immunity, and proliferation. In the liver, TNF exerts autocrine and paracrine effects that mediate a variety of pathophysiological states that involve liver injury and cell death and/or hepatocellular proliferation. Thus, TNF is a central regulator of hepatic physiology and delineation of the complex signaling pathways that mediate the disparate effects of this cytokine has contributed to our understanding of its function. In particular, investigations have attempted to determine how this factor could promote either cell proliferation or death in hepatocytes under different physiologic circumstances. With these studies has come an increased understanding of the complex events that determine whether a hepatocyte undergoes apoptosis or proliferation following TNF stimulation. This chapter will focus initially on signaling events that follow TNF ligand-receptor interaction, and subsequently on the precise functions of TNF signaling in specific pathophysiologic states. Although considerable progress has been made in defining TNF signaling pathways in hepatocytes, the challenge remains to determine how these signal cascades regulate disease states in order to mani-pulate these pathways for the treatment of human liver diseases.
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