NF-kappa B determines between apoptosis and proliferation in hepatocytes during liver regeneration

Tumor necrosis factor (TNF)-alpha is a potent inducer of apoptotic cell dea th in various tissues, whereas the transcription factor nuclear factor (NF) -kappa B is essential to protect against TNF-alpha-induced apoptosis. Human hepatoma cell lines were used to investigate the effectiveness and specifi city of the fungal metabolite gliotoxin in inhibiting TNF-alpha-induced NF- kappa B activation in transformed cells. Gliotoxin-TNF-alpha cotreatment in duced massive apoptosis in these otherwise TNF-alpha-resistant cell lines. With the use of the mouse partial hepatectomy model, we were also able to d emonstrate in vivo the capacity of gliotoxin to act as inhibitor of NF-kapp a B activation. Bromodeoxyuridine staining of liver sections showed that th e lack of NF-kappa B activation correlated with 80% reduction of DNA synthe sis 48 h after hepatectomy compared with untreated controls. Additionally, animals treated with gliotoxin showed nuclear condensation and DNA ladderin g of hepatocytes indicative of apoptosis 24 h after hepatectomy. In summary , our results demonstrate that NF-kappa B is essential in defining the fate of liver cells in response to TNF-alpha in vivo and furthermore implicate gliotoxin as a potential new response modifier for TNF-alpha-based therapy.