Pleiotropic functions of TNF-α determine distinct IKKβ-dependent hepatocellular fates in response to LPS

Pleiotropic functions of TNF-alpha determine distinct IKK beta-dependent hepatocellular fates in response to LPS. Am J Physiol Gastrointest Liver Physiol 292: G242-G252, 2007. First published August 24, 2006; doi:10.1152/ajpgi.00043.2006.-TNF-alpha influences morbidity and mortality during the course of endotoxemia. However, the complex pleiotropic functions of TNF-alpha remain poorly understood. We evaluated how hepatic induction of NF-kappa B and TNF-alpha influence survival and hepatocellular death in a lethal murine model of endotoxic shock. Using dominant-negative viral vectors to inhibit the IKK complex, we demonstrate through this study that the liver is a major source of TNF-alpha during the course of lethal endotoxemia and that IKK beta (but not IKK alpha) is predominantly responsible for activating NF-kappa B and TNF-alpha in the liver after LPS administration. Using TNF-alpha knockout mice and hepatic-specific inhibition of IKK beta, we demonstrate that the status of TNF-alpha and NF-kappa B balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF-alpha, inhibiting hepatic IKK beta resulted in increased survival, reduced serum proinflammatory cytokines, and reduced hepatocyte necrosis in response to a lethal dose of endotoxin. In contrast, inhibiting hepatic IKK beta in TNF-alpha knockout mice resulted in decreased survival and increased caspase 3-mediated hepatocyte apoptosis after endotoxin challenge, despite a reduced proinflammatory cytokine response. In the presence of TNF-alpha, NF-kappa B- dependent hepatocellular necrosis predominated, while in the absence of TNF-alpha, NF-kappa B primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation after LPS challenge were also dynamically affected by both IKK beta and TNF-alpha; however, this pathway could not solely explain the differential outcomes in hepatocellular fates. In conclusion, our studies demonstrate that induction of NF-kappa B and TNF-alpha balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.