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From the Department of Pathology,*
the School of
Medicine, and the Department of Environmental
Health,
the School of Public Health, the
University of Washington, Seattle, Washington
Tumor necrosis factor (TNF) is a mediator of the acute phase
response in the liver and can initiate proliferation and cause cell
death in hepatocytes. We investigated the mechanisms by which TNF
causes apoptosis in hepatocytes focusing on the role of oxidative
stress, antioxidant defenses, and mitochondrial damage.
The studies were conducted in cultured AML12 cells, a line of
differentiated murine hepatocytes. As is the case for hepatocytes
in vivo, AML12 cells were not sensitive to cell
death by TNF alone, but died by apoptosis when exposed to TNF
and a small dose of actinomycin D (Act D). Morphological signs of
apoptosis were not detected until 6 hours after the treatment and by 18
hours ~50% of the cells had died. Exposure of the cells to TNF+Act D
did not block NF
B nuclear translocation, DNA
binding, or its overall transactivation capacity. Induction of
apoptosis was characterized by oxidative stress indicated by the loss
of NAD(P)H and glutathione followed by mitochondrial damage that
included loss of mitochondrial membrane potential, inner
membrane structural damage, and mitochondrial condensation.
These changes coincided with cytochrome C release and the activation of
caspases-8, -9, and -3. TNF-induced apoptosis was
dependent on glutathione levels. In cells with decreased levels of
glutathione, TNF by itself in the absence of transcriptional
blocking acted as an apoptotic agent. Conversely, the
antioxidant 
-lipoic acid, that protected against the loss of
glutathione in cells exposed to TNF+Act D completely prevented
mitochondrial damage, caspase activation, cytochrome C
release, and apoptosis. The results demonstrate that apoptosis
induced by TNF+Act D in AML12 cells involves oxidative injury and
mitochondrial damage. As injury was regulated to a larger extent by the
glutathione content of the cells, we suggest that the
combination of TNF+Act D causes apoptosis because Act D blocks the
transcription of genes required for antioxidant defenses.
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