World journal of gastroenterology

Caspase-12 mediates carbon tetrachloride-induced hepatocyte apoptosis in mice.

PMID 25561786


To investigate the role of caspase-12 and its downstream targets in carbon tetrachloride (CCl4)-induced hepatocyte apoptosis. The role of caspase-12 was determined by using caspase-12 knock-out ((-/-)) mice. CCl4 (300 μL/kg body weight) or vehicle (corn oil) was administered to caspase-12(+/+) or caspase-12(-/-) mice as a single intraperitoneal injection. The animals were sacrificed 24 h after the CCl4 treatment. Blood was collected to evaluate liver function by the measurement of the activity of alanine aminotransferase. Liver samples were used for the measurements of reactive oxygen species using plasma malondialdehyde as biomarker, hepatocyte apoptosis was evaluated via terminal transferase-mediated dUTP nick-end labeling and controlled by morphologic study, and cytochrome C release and caspase activations were measured by Western blotting. Administration of a low dose of CCl4 resulted in hepatocyte apoptosis and acute liver injury in wild-type mice. CCl4 also induced the generation of reactive oxygen species and induction of endoplasmic reticulum stress in the liver followed by activations of caspase-12, -9 and -3 as well as release of small amounts of cytochrome C. However, in the CCl4-treated caspase-12(-/-) mice, activation of caspase-9 and -3 were significantly attenuated (P < 0.05); no effect was seen in cytochrome C release. CCl4-induced apoptosis and liver damage was markedly reduced in caspase-12(-/-) mice compared to caspase-12(+/+) mice (P < 0.05). The active form of caspase-8 was not detected in either caspase-12(+/+) or caspase-12(-/-) mice. There was no significant different in the formation of reactive oxygen species in the livers of caspase-12(+/+) and caspase-12(-/-) mice treated with CCl4. Caspase-12 plays a pivotal role in CCl4-induced hepatic apoptosis through the activation of the downstream effector caspase-3 directly and/or indirectly via caspase-9 activation.