A Ribosomal S-6 Kinase–Mediated Signal to C/EBP-β Is Critical for the Develo

StephenW

A Ribosomal S-6 Kinase–Mediated Signal to C/EBP-β Is Critical for the Development of Liver Fibrosis
Full paper http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001372

Background
In response to liver injury, hepatic stellate cell (HSC) activation causes excessive liver fibrosis. Here we show that activation of RSK and phosphorylation of C/EBPβ on Thr217 in activated HSC is critical for the progression of liver fibrosis.
Methodology/Principal Findings
Chronic treatment with the hepatotoxin CCl4 induced severe liver fibrosis in C/EBPβ+/+mice but not in mice expressing C/EBPβ-Ala217, a non-phosphorylatableRSK-inhibitory transgene. C/EBPβ-Ala217 was present within the deathreceptor complex II, with active caspase 8, and induced apoptosis ofactivated HSC. The C/EBPβ-Ala217 peptides directly stimulated caspase 8activation in a cell-free system. C/EBPβ+/+ mice with CCl4-induced severe liver fibrosis, while continuing on CCl4,were treated with a cell permeant RSK-inhibitory peptide for 4 or 8weeks. The peptide inhibited RSK activation, stimulating apoptosis ofHSC, preventing progression and inducing regression of liver fibrosis.We found a similar activation of RSK and phosphorylation of humanC/EBPβ on Thr266 (human phosphoacceptor) in activated HSC in patientswith severe liver fibrosis but not in normal livers, suggesting thatthis pathway may also be relevant in human liver fibrosis.
Conclusions/Significance

Thesedata indicate that the RSK-C/EBPβ phosphorylation pathway is criticalfor the development of liver fibrosis and suggest a potentialtherapeutic target.

[From Google Translate - not 100% accurate]

一个核糖体的S - 6激酶介导的信号到C / EBP的-β是为肝纤维化的发展关键
论文全文http://www.plosone.org/article/info％3Adoi％2F10.1371％2Fjournal.pone.0001372

背景

在回答肝损伤，肝星状细胞（HSC）的激活导致过度肝纤维化。在这里，我们表明，在Thr217的克拉伊纳共和国和C /EBPβ的磷酸化激活的HSC活化是肝纤维化的进展至关重要。
方法论/主要发现

治疗慢性四氯化碳诱导的hepatotoxin在C /EBPβ+ / +小鼠肝纤维化严重，但没有在小鼠表达C/EBPβ-Ala217，非phosphorylatable克拉伊纳共和国的抑制基因。 C/EBPβ-Ala217出席在死亡受体复合物Ⅱ，具有活性caspase 8和活化HSC诱导细胞凋亡。该C/EBPβ-Ala217肽直接刺激的无细胞系统蛋白酶8活化。的C /EBPβ+ /与四氯化碳诱导的肝纤维化严重，同时继续对四氯化碳，均与细胞透性克拉伊纳共和国的抑制为4或8周肽治疗+小鼠。肽抑制RSK的活化，刺激的HSC凋亡，防止恶化和诱导肝纤维化的回归。我们发现/EBPβ的活化HSC的Thr266（人类phosphoacceptor）严重肝纤维化的病人，但类似的RSK的活化和人类C磷酸化在正常肝脏，这表明这种途径也可以在人体肝脏纤维化有关。
结论/意义

这些数据表明，RSK-C/EBPβ磷酸化途径是为肝纤维化发展的关键，并提出一个潜在的治疗靶点。

StephenW

回复 花香半醉 的帖子

这项研究是为了防止和扭转纤维化(肝硬化).