title: Proliferation of mouse liver stem/progenitor cells induced by plasma from patients with acute liver failure is modulated by P2Y2 receptor-mediated JNK activation.
abstract: 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.
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, Japan, tingwang@iwate-med.ac.jp.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takikawa
authors.forename: Asako
authors.initials: A
authors.lastname: Watanabe
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kakisaka
authors.forename: Kanta
authors.initials: K
authors.lastname: Oikawa
authors.forename: Kanta
authors.initials: K
authors.lastname: Oigawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver; D017114:Liver Failure, Acute / Q000097:blood*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020239:Receptor Cross-Talk / Q000502:physiology; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058473:Receptors, Purinergic P2Y2; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases