Inhibition of tumor necrosis factor-induced apoptosis in transgenic mouse liver expressing creatine kinase.

BACKGROUND

The mitochondrion acts as a pivotal decision center in many types of apoptotic responses. To clarify the effects of the enhanced mitochondrial function on tumor necrosis factoralpha (TNFalpha)-induced apoptosis, we studied hepatic injuries in transgenic mice whose livers express creatine kinase (CK).

METHODS

Mice fed a diet containing 10% creatine, came to accumulate phosphocreatine and to enhance hepatic ATP levels and mitochondrial oxidative phosphorylation activities. TNFalpha-mediated hepatic apoptosis in normally fed and Cr-feeding CK transgenic mice were assessed.

RESULTS

TNFalpha and actinomycin D cause severe liver failure in normally fed transgenic mice, and in the wild-type mice. In contrast, no significant elevations in transaminase levels after injection were observed in Cr feeding transgenic mice. The disruption of the mitochondrial transmembrane potential at 2 h after TNFalpha injection, prior to ATP depletion, activation of caspase 3 like protease, and DNA fragmentation at 4-6 h after injection, were observed in normally fed transgenic mice. These were fully suppressed in Cr feeding transgenic mice. However, anti-Fas antibody-induced apoptosis was not inhibited in both groups.

CONCLUSIONS

The results indicate that TNFalpha-induced apoptosis was inhibited in CK transgenic mice livers by maintaining mitochondrial function.