The epidermal growth factor receptor ligand amphiregulin is a negative regulator of hepatic acute-phase gene expression.
OBJECTIVE
The modulation of the hepatic acute-phase reaction (APR) that occurs during inflammation and liver regeneration is important for allowing normal hepatocellular proliferation and the restoration of homeostasis. Activation of acute-phase protein (APP) gene expression by interleukin-6 (IL-6)-type cytokines is thought to be counteracted by growth factors released during hepatic inflammation and regeneration. The epidermal growth factor receptor (EGFR) ligand amphiregulin (AR) is readily induced by inflammatory signals and plays a nonredundant protective role during liver injury. In this paper, we investigated the role of AR as a modulator of liver APP gene expression.


METHODS
Expression of APP genes was measured in the livers of AR(+/+) and AR(-/-)mice during inflammation and regeneration and in cultured liver cells treated with AR and oncostatin M (OSM). Crosstalk between AR and OSM signalling was studied.


RESULTS
APP genes were overexpressed in the livers of AR(-/-) mice during inflammation and hepatocellular regeneration. In cultured AR-null hepatocytes and human hepatocellular carcinoma (HCC) cells after AR knockdown, APP gene expression is enhanced. AR counteracts OSM-triggered signal transducer and activator of transcription 3 signalling in hepatocytes and attenuates APP gene transcription.


CONCLUSIONS
Our data support the relevance of EGFR-mediated signalling in the modulation of cytokine-activated pathways. We have identified AR as a key regulator of hepatic APP gene expression during inflammation and liver regeneration.
Pardo-Saganta
Ana
A
Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda. Pio XII n. 55, 31008 Pamplona, Spain.
Latasa
Maria Ujue
MU
Castillo
Josefa
J
Alvarez-Asiain
Laura
L
Perugorría
María J
MJ
Sarobe
Pablo
P
Rodriguez-Ortigosa
Carlos M
CM
Prieto
Jesús
J
Berasain
Carmen
C
Santamaría
Mónica
M
Avila
Matías A
MA
D000209:Acute-Phase Proteins / Q000235:genetics*; D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D066258:Amphiregulin; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053683:Oncostatin M / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000514:alpha 1-Antichymotrypsin / Q000235:genetics
C587848:AREG protein, human; D000209:Acute-Phase Proteins; D066258:Amphiregulin; C587849:Areg protein, mouse; D017931:DNA Primers; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000514:alpha 1-Antichymotrypsin; D053683:Oncostatin M; D066246:ErbB Receptors