Pleiotropic functions of TNF-alpha determine distinct IKKbeta-dependent hepatocellular fates in response to LPS.
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-kappaB 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 IKKbeta (but not IKKalpha) is predominantly responsible for activating NF-kappaB and TNF-alpha in the liver after LPS administration. Using TNF-alpha knockout mice and hepatic-specific inhibition of IKKbeta, we demonstrate that the status of TNF-alpha and NF-kappaB balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF-alpha, inhibiting hepatic IKKbeta resulted in increased survival, reduced serum proinflammatory cytokines, and reduced hepatocyte necrosis in response to a lethal dose of endotoxin. In contrast, inhibiting hepatic IKKbeta 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-kappaB-dependent hepatocellular necrosis predominated, while in the absence of TNF-alpha, NF-kappaB primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation after LPS challenge were also dynamically affected by both IKKbeta 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-kappaB and TNF-alpha balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.
Dajani
Rana
R
Department of Anatomy and Cell Biology, University of Iowa, College of Medicine, 51 Newton Rd., Rm. 1-111 BSB, Iowa City, IA 52242, USA.
Sanlioglu
Salih
S
Zhang
Yulong
Y
Li
Qiang
Q
Monick
Martha M
MM
Lazartigues
Eric
E
Eggleston
Timothy
T
Davisson
Robin L
RL
Hunninghake
Gary W
GW
Engelhardt
John F
JF
D000818:Animals; D017209:Apoptosis; D019446:Endotoxemia / Q000473:pathology / Q000517:prevention & control; D004926:Escherichia coli; D051550:I-kappa B Kinase / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000097:blood / Q000235:genetics; D009336:Necrosis; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse