Buck Martina, Chojkier Mario
Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California, United States of America.
PLoS One. 2007 Dec 26;2(12):e1372. doi: 10.1371/journal.pone.0001372.
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/EBPbeta on Thr217 in activated HSC is critical for the progression of liver fibrosis.
METHODOLOGY/PRINCIPAL FINDINGS: Chronic treatment with the hepatotoxin CCl(4) induced severe liver fibrosis in C/EBPbeta(+/+) mice but not in mice expressing C/EBPbeta-Ala217, a non-phosphorylatable RSK-inhibitory transgene. C/EBPbeta-Ala217 was present within the death receptor complex II, with active caspase 8, and induced apoptosis of activated HSC. The C/EBPbeta-Ala217 peptides directly stimulated caspase 8 activation in a cell-free system. C/EBPbeta(+/+) mice with CCl(4)-induced severe liver fibrosis, while continuing on CCl(4), 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/EBPbeta 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.
CONCLUSIONS/SIGNIFICANCE: These data indicate that the RSK-C/EBPbeta phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target.
为应对肝损伤，肝星状细胞（HSC）激活会导致肝脏过度纤维化。在此我们表明，激活的HSC中RSK的激活以及C/EBPβ在苏氨酸217位点的磷酸化对于肝纤维化的进展至关重要。
方法/主要发现：用肝毒素CCl₄进行慢性处理在C/EBPβ（+/+）小鼠中诱导出严重肝纤维化，但在表达C/EBPβ-Ala217（一种不可磷酸化的RSK抑制转基因）的小鼠中未诱导出。C/EBPβ-Ala217存在于死亡受体复合物II中，与活性半胱天冬酶8在一起，并诱导激活的HSC凋亡。C/EBPβ-Ala217肽在无细胞系统中直接刺激半胱天冬酶8的激活。患有CCl₄诱导的严重肝纤维化的C/EBPβ（+/+）小鼠在继续使用CCl₄的同时，用一种细胞穿透性RSK抑制肽处理4周或8周。该肽抑制RSK激活，刺激HSC凋亡，阻止肝纤维化进展并诱导其消退。我们发现在严重肝纤维化患者激活的HSC中存在与人类C/EBPβ在苏氨酸266位点（人类磷酸化位点）类似的RSK激活和磷酸化，而在正常肝脏中未发现，这表明该途径可能在人类肝纤维化中也相关。
结论/意义：这些数据表明RSK-C/EBPβ磷酸化途径对于肝纤维化的发展至关重要，并提示了一个潜在的治疗靶点。
