Proliferation of mouse liver stem/progenitor cells induced by plasma from patients with acute liver failure is modulated by P2Y2 receptor-mediated JNK activation.

BACKGROUND: We recently reported that acute liver failure plasma (ALF-P) promotes the proliferation of mouse liver oval cells (OCs) through c-jun N-terminal kinase (JNK) activation. The aim of this study was to investigate the mechanism by which ALF-P induces JNK activation and OC proliferation.
METHODS: OCs and primary hepatocytes were exposed to ALF-P or normal control plasma (NC-P). Cell proliferation and activation of JNK and other JNK signaling molecules were detected subsequently. Next, we determined the effects of extracellular adenosine triphosphate (ATP) and ATP receptors on ALF-P-stimulated cell growth. Finally, the relationship between the tumor necrosis factor alpha (TNFα) and ATP receptor pathways was investigated.
RESULTS: Cell proliferation accompanied by JNK activation was only observed in ALF-P-stimulated OCs. ALF-P stimulated the activation of SEK1/MKK4 and ATF2, but not c-Jun. Both PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) treatment and P2Y2 (G-protein-coupled) small interfering RNA (siRNA) transfection blocked the effects of ALF-P on cell proliferation and JNK activation. However, ATP levels in ALF-P were significantly lower than that in NC-P, and ATP did not stimulate the proliferation of OCs. On the other hand, TNFα stimulated JNK activation and proliferation of OCs. TNFα receptor antagonist partly inhibited the ALF-P-stimulated proliferation of OCs. Moreover, PPADS significantly inhibited TNFα-stimulated cell proliferation, induced apoptosis, and inhibited the activation of JNK. However, our data showed no significant difference in plasma TNFα levels between the NC-P and ALF-P samples.
CONCLUSIONS: JNK activation induced by P2Y2 receptor crosstalk with the TNFα signaling pathway is important in mediating the effects of ALF-P on the proliferation and survival of OCs.