The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis.
The hepatic wound-healing response to chronic noxious stimuli may lead to liver fibrosis, a condition characterized by excessive deposition of extracellular matrix. Fibrogenic cells, including hepatic stellate cells and myofibroblasts, are activated in response to a variety of cytokines, growth factors, and inflammatory mediators. The involvement of members of the epidermal growth factor family in this process has been suggested. Amphiregulin (AR) is an epidermal growth factor receptor (EGFR) ligand specifically induced upon liver injury. Here, we have addressed the in vivo role of AR in experimental liver fibrosis. To this end, liver fibrosis was induced in AR+/+ and AR-/- mice by chronic CCl(4) administration. Histological and molecular markers of hepatic fibrogenesis were measured. Additionally, the response of cultured human and mouse liver fibrogenic cells to AR was evaluated. We observed that AR was expressed in isolated Kupffer cells and liver fibrogenic cells in response to inflamatory stimuli and platelet-derived growth factor, respectively. We demonstrate that the expression of alpha-smooth muscle actin and collagen deposition were markedly reduced in AR-/- mice compared to AR+/+ animals. AR-/- mice also showed reduced expression of tissue inhibitor of metalloproteinases-1 and connective tissue growth factor, two genes that responded to AR treatment in cultured fibrogenic cells. AR also stimulated cell proliferation and exerted a potent antiapoptotic effect on isolated fibrogenic cells.


CONCLUSIONS
These results indicate that among the different EGFR ligands, AR plays a specific role in liver fibrosis. AR may contribute to the expression of fibrogenic mediators, as well as to the growth and survival of fibrogenic cells. Additionally, our data lend further support to the role of the EGFR system in hepatic fibrogenesis.
Perugorria
Maria J
MJ
Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain.
Latasa
M Ujue
MU
Nicou
Alexandra
A
Cartagena-Lirola
Hugo
H
Castillo
Josefa
J
Goñi
Saioa
S
Vespasiani-Gentilucci
Umberto
U
Zagami
Maria G
MG
Lotersztajn
Sophie
S
Prieto
Jesús
J
Berasain
Carmen
C
Avila
Matias A
MA
D066258:Amphiregulin; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002251:Carbon Tetrachloride; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D002251:Carbon Tetrachloride; D066246:ErbB Receptors