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.
Department of Gastroenterological Surgery, Kyoto University, Graduate School of Medicine, Sakyo-ku, Japan. etsu@kuhp.kyoto-u.ac.jp
Etsuro
E
Hatano
Akira
A
Tanaka
Akiyoshi
A
Kanazawa
Shigeru
S
Tsuyuki
Shoji
S
Tsunekawa
Shingo
S
Iwata
Rei
R
Takahashi
Britton
B
Chance
Yoshio
Y
Yamaoka
D000225:Adenine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003402:Creatine Kinase / Q000235:genetics*; D053938:DNA Fragmentation / Q000502:physiology*; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D017093:Liver Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000225:Adenine