Shuh, Maureen; Bohorquez, Humberto; Loss, George E., Jr.; Cohen, Ari J.
Background: Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine involved in a variety of disease pathologies, including ischemia/reperfusion (I/R) injuries in transplantation. The interaction of TNF-alpha with its cognate receptor TNF receptor I (TNFRI) results in the activation of signal transduction pathways that regulate either cell survival or cell death. Hepatocytes express TNFRI and respond to TNF-alpha released by resident Kupffer cells as well as leukocytes that migrate to the liver during I/R injury. Upon binding TNF-alpha, the hepatocyte proliferates or undergoes apoptosis or necroptosis. The decision by the cell to commit to one path or the other is not understood. The damaged tissue exhibits cell death and hemorrhaging from the influx of immune mediators. TNF-alpha inhibitors ameliorate the injury in animal models, suggesting that lowering (but not eliminating) TNF-alpha levels shifts the balance of TNF-alpha toward its beneficial functions.; Methods: We review TNF-alpha signal transduction pathways and the role of TNF-alpha in liver I/R injury.; Conclusions: Because TNF-alpha plays an important role in hepatocyte proliferation, complete inhibition of TNF-alpha is not desirable in treating liver I/R injury. The strategy for developing pharmacological therapies may be the identification of specific intermediates in the TNF-alpha/TNFR1 signal transduction pathway and directed targeting of proapoptotic and pronecroptotic events.