Proliferation of mouse liver stem/progenitor cells induced by plasma from patients with acute liver failure is modulated by P2Y2 receptor-mediated JNK activation
Proliferation of mouse liver stem/progenitor cells induced by plasma from patients with acute liver failure is modulated by P2Y2 receptor-mediated JNK activation
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DOI：
10.1007/s00535-013-0927-6
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发表时间：
2014-02
影响因子：
6.3
通讯作者：
Ting Wang;Y. Takikawa;A. Watanabe;Keisuke Kakisaka;Kanta Oigawa;Y. Miyamoto;Kazuyuki Suzuki
中科院分区：
文献类型：
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作者：
Ting Wang;Y. Takikawa;A. Watanabe;Keisuke Kakisaka;Kanta Oigawa;Y. Miyamoto;Kazuyuki Suzuki
背景我们最近报道了急性肝衰竭血浆（acuteliveplaserplasma，ALF-P）通过激活c-jun N-末端激酶（c-jun N-terminalkinase，JNK）促进小鼠肝卵圆细胞（OCs）增殖。本研究的目的是探讨ALF-P诱导JNK激活和OC增殖的机制。方法OC和原代肝细胞暴露于ALF-P或正常对照血浆（NC-P）。随后检测细胞增殖和JNK及其他JNK信号分子的活化。接下来，我们确定了细胞外三磷酸腺苷（ATP）和ATP受体对ALF-P刺激的细胞生长的影响。最后，肿瘤坏死因子α（TNFα）和ATP受体通路之间的关系进行了调查。结果细胞增殖伴随JNK激活只观察到ALF-P刺激OC。PPADS（pyridoxalphosphate-6-azophenyl-2′，4 ′-disulfonic acid，吡哆醛磷酸-6-偶氮苯-2 ′，4 ′-二磺酸）处理和P2 Y2（G蛋白偶联）小干扰RNA（siRNA）转染均阻断ALF-P对细胞增殖和JNK激活的影响。但ALF-P组的ATP水平明显低于NC-P组，且ATP对OC的增殖无刺激作用。另一方面，TNFα刺激JNK活化和OC增殖。TNFα受体拮抗剂可部分抑制ALF-P刺激的OC增殖。PPADS可显著抑制TNFα刺激的细胞增殖，诱导细胞凋亡，并抑制JNK的激活。结论P2 Y2受体与TNFα信号通路相互作用诱导JNK活化，在ALF-P调节OC增殖和存活中起重要作用。
BackgroundWe 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.MethodsOCs 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.ResultsCell 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.ConclusionsJNK activation induced by P2Y2receptor crosstalk with the TNFα signaling pathway is important in mediating the effects of ALF-P on the proliferation and survival of OCs.