Implication of cytokines: Roles of tumor necrosis factor-α in liver injury

Acute liver failure caused by viruses, drugs, or liver resection, is marked by a massive degree of hepatocyte apoptosis and impaired hepatocyte proliferation, the mechanisms of which, however, still remain to be understood. The choice between life and death is associated with events in regulation of the immune system. The liver is continuously exposed to a large antigenic load that includes pathogens, toxins and dietary antigens. Bacterial toxins, including endotoxin and staphylococcal enterotoxin, have been implicated in the pathogenesis of multi-organ failure associated with liver damage through production of cytokines and chemokines. Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Among pro-inflammatory mediators, tumor necrosis factor-alpha (TNF-alpha)/TNF receptor (TNFR) systems play central roles in the physiological regulation of apoptosis as well as inflammation and immunity. These pleiotropic biological effects of TNF-alpha result from its ability to initiate different intracellular signaling pathways, which induce both pro-apoptotic and anti-apoptotic molecules. Hepatocytes appear to be poorly responsive to pro-apoptotic stimuli by TNF-alpha. Tumor necrosis factor-alpha, however, induces excessive hepatocyte apoptosis, once cells are sensitized by D-galactosamine or actinomycin D, suggesting that TNF-alpha itself also induces molecules that protect cells from apoptosis by TNF-alpha. Besides the apoptosis-inducing signal, the binding of TNF-alpha to TNFR1 triggers a series of intracellular events that result in the activation of nuclear factor-kappa B (NF-kappa B), phosphatidylinositol 3-kinase (PI3K)/Akt, and c-Jun NH2-terminal kinase (JNK). Inhibition of NF-kappa B may be a two-edged sword against liver injury, which inhibits pro-inflammatory gene expression in leukocytes and causes the sensitization of hepatocytes to TNF-alpha-induced apoptosis. A variety of mechanisms exist to modulate the activity of intracellular molecules and thereby affect the ultimate outcome of a liver cell's fate.