Journal article
Pleiotropic functions of TNF-α determine distinct IKKβ-dependent hepatocellular fates in response to LPS
American journal of physiology: Gastrointestinal and liver physiology, Vol.292(1), pp.G242-G252
01/2007
DOI: 10.1152/ajpgi.00043.2006
PMID: 16935850
Abstract
TNF-α influences morbidity and mortality during the course of endotoxemia. However, the complex pleiotropic functions of TNF-α remain poorly understood. We evaluated how hepatic induction of NF-κB and TNF-α 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-α during the course of lethal endotoxemia and that IKKβ (but not IKKα) is predominantly responsible for activating NF-κB and TNF-α in the liver after LPS administration. Using TNF-α knockout mice and hepatic-specific inhibition of IKKβ, we demonstrate that the status of TNF-α and NF-κB balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF-α, inhibiting hepatic IKKβ resulted in increased survival, reduced serum proinflammatory cytokines, and reduced hepatocyte necrosis in response to a lethal dose of endotoxin. In contrast, inhibiting hepatic IKKβ in TNF-α 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-α, NF-κB-dependent hepatocellular necrosis predominated, while in the absence of TNF-α, NF-κB primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation after LPS challenge were also dynamically affected by both IKKβ and TNF-α; however, this pathway could not solely explain the differential outcomes in hepatocellular fates. In conclusion, our studies demonstrate that induction of NF-κB and TNF-α balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.
Details
- Title: Subtitle
- Pleiotropic functions of TNF-α determine distinct IKKβ-dependent hepatocellular fates in response to LPS
- Creators
- Rana DajaniSalih SanliogluYulong ZhangQiang LiMartha M MonickEric LazartiguesTimothy EgglestonRobin L DavissonGary W HunninghakeJohn F Engelhardt
- Resource Type
- Journal article
- Publication Details
- American journal of physiology: Gastrointestinal and liver physiology, Vol.292(1), pp.G242-G252
- DOI
- 10.1152/ajpgi.00043.2006
- PMID
- 16935850
- ISSN
- 0193-1857
- eISSN
- 1522-1547
- Language
- English
- Date published
- 01/2007
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pulmonary, Critical Care, and Occupational Medicine; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984025351202771
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