NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration.
Tumor necrosis factor (TNF)-alpha is a potent inducer of apoptotic cell death in various tissues, whereas the transcription factor nuclear factor (NF)-kappaB is essential to protect against TNF-alpha-induced apoptosis. Human hepatoma cell lines were used to investigate the effectiveness and specificity of the fungal metabolite gliotoxin in inhibiting TNF-alpha-induced NF-kappaB activation in transformed cells. Gliotoxin-TNF-alpha cotreatment induced massive apoptosis in these otherwise TNF-alpha-resistant cell lines. With the use of the mouse partial hepatectomy model, we were also able to demonstrate in vivo the capacity of gliotoxin to act as inhibitor of NF-kappaB activation. Bromodeoxyuridine staining of liver sections showed that the lack of NF-kappaB activation correlated with 80% reduction of DNA synthesis 48 h after hepatectomy compared with untreated controls. Additionally, animals treated with gliotoxin showed nuclear condensation and DNA laddering of hepatocytes indicative of apoptosis 24 h after hepatectomy. In summary, our results demonstrate that NF-kappaB 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.
Plümpe
J
J
Department of Gastroenterology and Hepatology, Medizinische Hochschule, 30625 Hannover, Germany.
Malek
N P
NP
Bock
C T
CT
Rakemann
T
T
Manns
M P
MP
Trautwein
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D004357:Drug Synergism; D005912:Gliotoxin / Q000494:pharmacology; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D005912:Gliotoxin; D004247:DNA