Synergism between Jnk1 and Jnk2 is a sine qua non condition for hepatic protection against toxicity

Abstract

Hepatocyte death, a feature of acute and chronic liver failure, is observable after acetoaminophen (APAP) poisoning in humans or LPS/GalN or CCl4-induced liver toxicity in mice. The activation of the c-Jun NH2 terminal kinase (JNK) intracellular signalling pathway during hepatocyte necrosis is a common molecular mechanism. In this context, the study of the shared functions of Jnk1 and Jnk2 in hepatocytes can be of utmost interest. Therefore, we generated mice with compound deletion of Jnk1 and Jnk2 in hepatocytes (JNKΔhepa) which were backcrossed several times to obtain the proper controls. All mice strains were subjected to experimental models of acute (APAP and LPS/GalN) and chronic liver injury (CCl4) respectively. Cell culture with primary isolated hepatocytes and hepatic stellate cells in the presence or absence of anti-apoptotic or anti-necrotic treatments was also performed. Finally, a microarray analysis was carried out to separate shared and distinct functions of Jnk1 and Jnk2. Gene analysis of JNKΔhepa shows that dual functions of Jnk1 and Jnk2 are necessary for correct liver function, included cell survival. The in vivo experimental models elicited that compound function of Jnk1 and Jnk2 in hepatocytes is a prerequisite for protection against acute or chronic liver-induced damage. Bone marrow transplants confirmed that only Jnk1 or Jnk2 are not sufficient for hepatic function. In vitro studies pointed at hepatocytes rather than hepatic stellate cells (HSCs) as main effectors of the combined JNK effect. Moreover, treatment of hepatocytes with necrostatin-1 in combination with a pan-Caspase inhibitor significantly increased hepatocyte survival. Our results deepen in understanding of the MAPK signalling pathway by eliciting a novel but synchronic function of Jnk1 and Jnk2 during acute and chronic liver damage.