Inhibition of nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor alpha in mice

Motoaki Imose, Masahito Nagaki, Takafumi Naiki, Yosuke Osawa, David A Brenner, Takahiko Asano, Hideki Hayashi, Tomohiro Kato, Hisataka Moriwaki
Liver International: Official Journal of the International Association for the Study of the Liver 2003, 23 (5): 386-96

BACKGROUND/AIMS: Tumor necrosis factor (TNF)-alpha itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF-alpha/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)-kappaB. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF-alpha. Here, we focused on the roles of NF-kappaB and phosphatidylinositol 3-kinase (PI3K)-regulated serine/threonine kinase Akt.

METHODS: TNF-alpha was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form IkappaBalpha (Ad5IkappaB), the PI3K inhibitor wortmannin, or both. Liver injury was assessed biochemically and histologically. The expression of Bcl-2 family members and caspase activity were examined.

RESULTS: In the mice livers, treatment with Ad5IkappaB or the wortmannin suppressed the activation of NF-kappaB or Akt, respectively. Suppression of either NF-kappaB or Akt showed a slight increase in transaminase levels and focal liver cell death after TNF-alpha administration. However, in mice treated with both Ad5IkappaB and wortmannin, TNF-alpha administration resulted in massive hepatocyte apoptosis and hemorrhagic liver destruction in mice. The combination of Ad5IkappaB, wortmannin, and TNF-alpha markedly increased the activation of caspase-3 and -9, and activated caspase-8 to a lesser degree, suggesting that TNF-alpha-induced hepatocyte apoptosis is dependent on type II cell death signaling pathway, probably through the mitochondria. Inhibition of the NF-kappaB and PI3K/Akt pathways had no effect on expression of Bcl-2 families.

CONCLUSION: The inducible activation of NF-kappaB and constitutive activation of Akt regulate hepatocyte survival against TNF-alpha, which occurs independent of Bcl-2 families.

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