ADAM17, induced by Augmenter of Liver Regeneration via G protein-coupled receptor activation, transactivates epidermal growth factor-receptor and reduces classical IL-6 signaling

Liver regeneration is orchestrated by various cytokines and growth factors, and any imbalance in this process may contribute to liver disease development. Augmenter of Liver Regeneration (ALR), an anti-apoptotic and anti-inflammatory co-mitogen supports regeneration, yet the molecular mechanisms by which ALR regulates proliferation and inflammation remain poorly understood. Hepatoma cell lines, primary mouse and human hepatocytes, and mice subjected to ischemia–reperfusion injury, were treated with recombinant ALR. Various specific inhibitors, small interfering RNA, immunoprecipitation, Western blot, qRT-PCR and ELISA techniques were utilized to analyze the underlying signaling pathways. ALR induces the phosphorylation of the EGF-receptor (EGF-R), which subsequently activates the MAPK and PI3K/Akt pathways. EGF-R phosphorylation is triggered by EGF-R ligands, such as TGFα, amphiregulin and HB-EGF, which are released from plasma membranes by the sheddase a disintegrin and metalloproteinase 17 (ADAM17) upon ALR activation. Furthermore, ALR-activated ADAM17 cleaves the membrane-tethered IL-6-receptor α (gp80), thereby reducing IL-6-induced STAT3 phosphorylation and the expression of its target genes (e.g. ICAM-1) in vitro and in vivo. The induction of ADAM17 involves the phosphorylation of protein kinase C (PKC) and the tyrosine kinase Src, as well as the activation of a G protein-coupled receptor (GPCR) by ALR. ALR transduction across plasma membranes is achieved by activating a Gαq/11-coupled GPCR, which is known to induce ADAM17 via cytosolic relay molecules PKC and Src. Activation of ADAM17 by ALR: i) transactivates EGF-R signaling upon release of membrane-bound EGF-R ligands, and ii) attenuates classical IL-6 signaling upon gp80 shedding. ALR supports liver regeneration by inducing EGF-R-dependent proliferative (MAPK) and anti-apoptotic (PI3K/Akt) pathways, and reduces IL-6-induced inflammatory gene expression.