A ribosomal S-6 kinase-mediated signal to C/EBP-beta is critical for the development of liver fibrosis.
A ribosomal S-6 kinase-mediated signal to C/EBP-beta is critical for the development of liver fibrosis.
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DOI：
10.1371/journal.pone.0001372
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发表时间：
2007-12-26
期刊：
影响因子：
3.7
通讯作者：
Chojkier, Mario
中科院分区：
文献类型：
--
作者：
Buck, Martina;Chojkier, Mario
肝星状细胞（HSC）活化导致肝纤维化过度。在此，我们发现活化的HSC中RSK的活化和Thr 217上C/EBPβ的磷酸化在肝纤维化的进展中是至关重要的。用肝毒素CCl 4慢性处理在C/EBPβ+/+小鼠中诱导了严重的肝纤维化，但在表达C/EBPβ-Ala 217（一种不可磷酸化的RSK抑制转基因）的小鼠中没有诱导。C/EBPβ-Ala 217存在于死亡受体复合物II中，与活化的caspase 8一起诱导活化的HSC凋亡。C/EBPβ-Ala 217肽在无细胞系统中直接刺激caspase 8活化。CCl 4诱导重度肝纤维化的C/EBPβ+/+小鼠，在继续接受CCl 4治疗的同时，用细胞渗透性RSK抑制肽治疗4或8周。该肽抑制RSK活化，刺激HSC凋亡，阻止肝纤维化的进展并诱导肝纤维化消退。我们发现，在严重肝纤维化患者的活化HSC中，RSK的活化和Thr 266（人磷酸化受体）上的人C/EBPβ的磷酸化相似，但在正常肝脏中没有，这表明该途径也可能与人类肝纤维化有关。这些数据表明RSK-C/EBPβ磷酸化途径对肝纤维化的发展至关重要，并提出了潜在的治疗靶点。
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. Chronic treatment with the hepatotoxin CCl4 induced severe liver fibrosis in C/EBPβ+/+ mice but not in mice expressing C/EBPβ-Ala217, a non-phosphorylatable RSK-inhibitory transgene. C/EBPβ-Ala217 was present within the death receptor complex II, with active caspase 8, and induced apoptosis of activated HSC. The C/EBPβ-Ala217 peptides directly stimulated caspase 8 activation 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 8 weeks. The peptide inhibited RSK activation, stimulating apoptosis of HSC, preventing progression and inducing regression of liver fibrosis. We found a similar activation of RSK and phosphorylation of human C/EBPβ on Thr266 (human phosphoacceptor) in activated HSC in patients with severe liver fibrosis but not in normal livers, suggesting that this pathway may also be relevant in human liver fibrosis. These data indicate that the RSK-C/EBPβ phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target.
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影响因子：
64.8
作者：
BRAVO, R;FRANK, R;MACDONALDBRAVO, H
通讯作者：
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影响因子：
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