A ribosomal S-6 kinase-mediated signal to C/EBP-beta 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/EBPbeta on Thr217 in activated HSC is critical for the progression of liver fibrosis.


RESULTS
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
These data indicate that the RSK-C/EBPbeta phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target.
Buck
Martina
M
Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, California, United States of America. mbuck@ucsd.edu
Chojkier
Mario
M
D000818:Animals; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002474:Cell-Free System; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D017931:DNA Primers; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction
D022782:CCAAT-Enhancer-Binding Protein-beta; D024042:Collagen Type I; D017931:DNA Primers; D019893:Ribosomal Protein S6 Kinases; D053181:Caspase 8