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LIVER AND BILIARY TRACT

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

¹Department of Anatomy and Cell Biology, ²Department of Internal Medicine-Division of Pulmonary and Critical Care, ³Center for Gene Therapy at the University of Iowa College of Medicine, Iowa City, Iowa; and ⁴Human Gene Therapy, Faculty of Medicine at the Akdeniz University, Antalya, Turkey

Submitted 24 January 2006 ; accepted in final form 23 August 2006

TNF- influences morbidity and mortality during the course of endotoxemia. However, the complex pleiotropic functions of TNF- remain poorly understood. We evaluated how hepatic induction of NF-B and TNF- 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- during the course of lethal endotoxemia and that IKK (but not IKK) is predominantly responsible for activating NF-B and TNF- in the liver after LPS administration. Using TNF- knockout mice and hepatic-specific inhibition of IKK, we demonstrate that the status of TNF- and NF-B balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF-, inhibiting hepatic IKK 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 in TNF- 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-, NF-B-dependent hepatocellular necrosis predominated, while in the absence of TNF-, NF-B primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation after LPS challenge were also dynamically affected by both IKK and TNF-; however, this pathway could not solely explain the differential outcomes in hepatocellular fates. In conclusion, our studies demonstrate that induction of NF-B and TNF- balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.

nuclear factor-B; endotoxic shock; inflammation; apoptosis; c-jun NH₂-terminal kinase