A Ribosomal S-6 Kinase-Mediated Signal to C/EBP-β Is Critical for the Development of Liver Fibrosis

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/EBP beta 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/EBP beta(+/+) mice but not in mice expressing C/EBP beta-Ala217, a non-phosphorylatable RSK-inhibitory transgene. C/EBP beta-Ala217 was present within the death receptor complex II, with active caspase 8, and induced apoptosis of activated HSC. The C/EBPb-Ala217 peptides directly stimulated caspase 8 activation in a cell-free system. C/EBP beta (+/+) 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/EBP beta 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/EBP beta phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target.