TNF-a induced hepatocyte apoptosis

Notably, in a study on mouse hepatocytes in vitro, D.A. Brenner and Y.Hannun confirmed that activation of ASMase and generation of eeramide (specifically of chain length Cl6) contributes to TNF-a-induced hepatocyte apoptosis (Osawa et al., 2005), but they did not see an involvement of downstream GD3 formation in their model. Another observation to be mentioned in this context is that TNF-a-induced apoptosis in the human myelogenous leukemia cells was blocked by the ASMase inhibitor SR33557 (Higuchi et al.,... 

If a single toxin releases TNF and simultaneously sensitizes cells towards the apoptotic actions of this cytokine, then TNF-induced hepatocyte apoptosis should contribute significantly to overall toxicity (see Fig. 5). For some toxins such a scenario has been demonstrated. For example, the toxicity of CCI4, the prototype of a directly acting hepatotoxin, is inhibited by scavenging of TNF with recombinant soluble TNF-receptor constructs (Czaja et al. 1995). 

Rolfe, M., James, N. H., and Roberts, R. A. (1997). Tumour necrosis factor al[4ia (TNF al[4ia) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes a mediator of the hepatocarcinogenicity of peroxisome proUferators Carcinogenesis 18, 2277-2280. 

Leist M, Gantner F, Bohlinger I, German PG, Tiegs G, Wendel A (1994) Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J Immunol 153 1778-1787... 

Fig. 1. Time course of cell death parameters in tumor necrosis factor (TNF)-induced apoptosis. Human hepatoma cells (HepG2) were incubated in the presence of 400 nM actinomycin D plus 1.6 ng/ml recombinant human TNF (rhTNF)-a. MTT-dye reduction (parameter of mitochondrial function), lactate dehydrogenase (LDH) release (parameter for cell membrane rupture), and DNA fragmentation (parameter associated with typically apoptotic nuclear changes) were determined over a time period of 24 h. As is characteristic of apoptotic cell death, DNA fragmentation always preceded the other death parameters. Similar findings have been obtained in primary hepatocyte cultures and murine livers...

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