The mitogenic activity of the liver growth factor is mediated by tumor necrosis factor alpha in rat liver

Background/Aims: Liver growth factor (LGF) is a hepatic mitogen, however, the hepatic stimulation pathway remains to be characterized. The aim of this study was to determine whether tumor necrosis factor alpha (TNF-α) stimulation constitutes a step in the mitogenic pathway of LGF. Methods: Rats were injected with 4.5 μg LGF/rat, and LGF activity was measured both by liver DNA synthesis stimulation and ‘proliferating cell nuclear antigen (PCNA)-positive’ hepatocytes in rats injected with LGF or +anti-TNF-α. TNF-α expression was evaluated by reverse-transcription polymerase chain reaction. TNF-α-producing cells were immunodetected. Human endothelial cells (HUVEC) were stimulated by LGF. TNF-α was detected in the supernatant, and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial adhesion molecule-1 (VCAM-1) by flow cytometry analysis. Results: LGF-injected rats showed higher intrahepatic TNF-α expression. DNA synthesis and PCNA-positive hepatocytes induced by LGF were inhibited by anti-TNF-α, PCNA-positive hepatocytes being especially abundant around the central vein when LGF was injected alone, but TNF-α exhibited increased signal intensity in endothelial cells of the portal vein. LGF stimulated TNF-α secretion in HUVEC, but did not stimulate ICAM-1 or VCAM-1 up-regulation. Conclusions: The mitogenic cascade initiated by LGF in rat liver in vivo depends, at least in part, on TNF-α stimulation. Portal vein endothelial cells seem to be a source of TNF-α.