The epidermal growth factor receptor ligand amphiregulin is a negative regulator of hepatic acute-phase gene expression☆

Background/Aims

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.

Abbreviations: APR, acute-phase reaction, APP, acute-phase protein, IL, interleukin, EGFR, epidermal growth factor receptor, AR, amphiregulin, OSM, oncostatin M, STAT, signal transducer and activator of transcription, TNF, tumour necrosis factor, JAK, Janus-activated kinase, TGF, transforming growth factor, HB-EGF, heparin-binding EGF-like growth factor, BTC, betacellulin, EREG, epiregulin, LPS, lipopolysaccharide, MEK1, extracellular regulated kinase kinase 1, ActD, actinomycin D, α1-ACT, α1-antichymotrypsin, SAA, serum amyloid A, AGP2, α1-acid glycoprotein 2, ERK, extracellular regulated kinase, SHP2, Src homology 2 domain-containing tyrosine phosphatase, SOCS, suppressor of cytokine signalling, siRNA, short interfering RNA, ChIP, chromatin immunoprecipitation, PH, partial hepatectomy

Keywords: Acute-phase proteins, Amphiregulin, Oncostatin, Liver regeneration