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01.12.2014 | Original Article—Liver, Pancreas, and Biliary Tract | Ausgabe 12/2014

Journal of Gastroenterology 12/2014

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

Zeitschrift:
Journal of Gastroenterology > Ausgabe 12/2014
Autoren:
Ting Wang, Yasuhiro Takikawa, Asako Watanabe, Keisuke Kakisaka, Kanta Oigawa, Yasuhiro Miyamoto, Kazuyuki Suzuki
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00535-013-0927-6) contains supplementary material, which is available to authorized users.
An erratum to this article can be found at http://​dx.​doi.​org/​10.​1007/​s00535-014-0939-x.

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.

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Zusatzmaterial
Supplemental data Table 1. Levels of various cytokines except TNFα in human plasma. Plasma cytokine levels were measured as described in Materials and Methods. Data are expressed as the mean ± SD (n = 3). *p < 0.05 versus control. (DOCX 19 kb)
535_2013_927_MOESM1_ESM.docx
Supplemental data Figure 1. Effects of ALF-P on the expression of OC marker genes. OCs were treated with ALF-P for 72 h. Gene expression of CK19, Alb, AFP, TAT and G6Pase was detected as described in Materials and Methods. GAPDH was used as an internal control. (JPEG 19 kb)
535_2013_927_MOESM2_ESM.jpg
Literatur
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