Novel role for amphiregulin in protection from liver injury.
Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.
Berasain
Carmen
C
Division of Hepatology and Gene Therapy, Centro de Investigación Médica Aplicada, Facultad de Medicina, Universidad de Navarra, Pío XII, 55, 31008 Pamplona, Spain.
García-Trevijano
Elena R
ER
Castillo
Josefa
J
Erroba
Elena
E
Santamaría
Mónica
M
Lee
David C
DC
Prieto
Jesús
J
Avila
Matías A
MA
D000410:Alanine Transaminase / Q000097:blood; D066258:Amphiregulin; D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000378:metabolism; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D022781:Hepatocytes / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis; D015854:Up-Regulation; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis
D066258:Amphiregulin; C587849:Areg protein, mouse; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D066255:EGF Family of Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006023:Glycoproteins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D051020:bcl-X Protein; D019014:fas Receptor; D004815:Epidermal Growth Factor; D012313:RNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D066246:ErbB Receptors; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases