Combined Stimulation with the Tumor Necrosis Factorαand the Epidermal Growth Factor Promotes the Proliferation of Hepatocytes in Rat Liver Cultured Slices
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Medientyp:
E-Artikel
Titel:
Combined Stimulation with the Tumor Necrosis Factorαand the Epidermal Growth Factor Promotes the Proliferation of Hepatocytes in Rat Liver Cultured Slices
Beschreibung:
<jats:p>The culture liver slices are mainly used to investigate drug metabolism and xenobiotic-mediated liver injuries while apoptosis and proliferation remain unexplored in this culture model. Here, we show a transient increase in LDH release and caspase activities indicating an ischemic injury during the slicing procedure. Then, caspase activities decrease and remain low in cultured slices demonstrating a low level of apoptosis. The slicing procedure is also associated with the G0/G1 transition of hepatocytes demonstrated by the activation of stress and proliferation signalling pathways including the ERK1/2 and JNK1/2/3 MAPKinases and the transient upregulation of c-fos. The cells further progress up to mid-G1 phase as indicated by the sequential induction of c-myc and p53 mRNA levels after the slicing procedure and at 24 h of culture, respectively. The stimulation by epidermal growth factor induces the ERK1/2 phosphorylation but fails to activate expression of late G1 and S phase markers such as cyclin D1 and Cdk1 indicating that hepatocytes are arrested in mid-G1 phase of the cell cycle. However, we found that combined stimulation by the proinflammatory cytokine tumor necrosis factor<jats:italic>α</jats:italic>and the epidermal growth factor promotes the commitment to DNA replication as observed<jats:italic>in vivo</jats:italic>during the liver regeneration.</jats:p>