Amphiregulin: an early trigger of liver regeneration in mice |
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Authors: | Berasain Carmen García-Trevijano Elena R Castillo Josefa Erroba Elena Lee David C Prieto Jesús Avila Matías A |
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Institution: | Division of Hepatology and Gene Therapy, Cntro de Investigción Médica Aplicada, Facultad e Medicina,Universidad de Navarra, Pamplona, Spain. |
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Abstract: | BACKGROUND AND AIMS: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. METHODS: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice. RESULTS: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1beta and prostaglandin E(2), but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor alpha. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection. CONCLUSIONS: Our findings indicate that amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration. |
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Keywords: | AR amphiregulin BrdU 5-bromo-2′-deoxyuridine CRE cyclic adenosine monophosphate-responsive element EGF epidermal growth factor EGF-R epidermal growth factor receptor ERK extracellular regulated kinase FCS fetal calf serum HB-EGF heparin-binding EGF-like growth factor HGF hepatocyte growth factor IL interleukin JNK c-Jun protein kinase MEK extracellular regulated kinase kinase p38 MAPK p38 mitogen-activated protein kinase PCNA proliferating cell nuclear antigen PCR polymerase chain reaction PGE2 prostaglandin E2 PH partial hepatectomy PI-3K phosphatidylinositol 3-kinase TGF transforming growth factor TNF tumor necrosis factor WT1 Wilms’ tumor suppressor 1 |
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