Differential Protective Roles of c-Jun N-terminal Kinase-2 in Nonparenchymal Liver Cells and Hepatocytes During Cholestasis.

BACKGROUND & AIMS: Cell-type-specific mechanisms are crucial in determining liver disease progression (eg, during cholestasis). Here, we defined the role of c-Jun N-terminal kinases 2 (JNK2) in cholestasis. Specifically, we studied differential JNK2 functions for controlling bile acid (BA) homeostasis and inflammation. METHODS: Mice lacking Jnk2 function, either specifically in hepatocytes (Jnk2(Δhepa)), globally (Jnk2(-/-)), or in combination with hepatocyte-specific Jnk1 deletion (Jnk1(Δhepa)/2(-/-)), were subjected to bile duct ligation (BDL). Parameters of liver injury, inflammation, BA composition, synthesis and transport, and fibrosis were studied. Additionally, bone marrow transplantation (BMT) experiments were performed. Furthermore, primary cultured hepatocytes were incubated with hyper-interleukin (IL)6, and hepatic BA transporters were analyzed. RESULTS: Jnk2(-/-) mice triggered increased liver injury, inflammation, and fibrosis compared with WT and Jnk2(Δhepa) mice after BDL. However, Jnk1(Δhepa)/2(-/-) mice exhibited an aggravated phenotype compared with Jnk2(-/-) livers as indicated by enhanced hepatic damage, ductular reaction, inflammatory response, and fibrogenesis. BMT experiments excluded BM-derived cells and indicated that nonparenchymal liver cells (NPCs) play a critical role in driving the Jnk1(Δhepa)/2(-/-)-dependent severe phenotype after BDL. Furthermore, in vivo and in vitro analysis demonstrated a pivotal role for JNK signaling in hepatocytes in the regulation of BA homeostasis and transport. CONCLUSIONS: Besides in hepatocytes, JNK2 in NPCs-but not in BM-derived cells-confers protection during cholestasis. After BDL, a JNK2-dependent mechanism directs the inflammatory response involved in regulating biliary transporters. Hence, our data define JNK2 as a critical target during cholestasis in NPCs.