patic-specific genes and antagonizes, in part, the action Our study addressed the role of the human hepatocyte of IL-6. (HEPATOLOGY 1996;23:1345-1352.) growth factor (HGF), a potent mitogen for mature rat and human hepatocytes, in the regulation of specific hepatic genes. The experimental evidence obtained in pri-The hepatocyte growth factor (HGF), a heterodimeric mary cultured human hepatocytes indicates that HGF molecule of 69 and 34 kd first isolated from rat plateregulates the synthesis of plasma proteins in a dose-re-lets, 1,2 was soon recognized to be a potent mitogen for sponse fashion. It stimulates the synthesis of the negarat hepatocytes. 3 The homologous human HGF was tive acute-phase proteins albumin, transferrin, and fisubsequently cloned and expressed as recombinant bronectin, decreases that of a 1 -antichymotrypsin (ACT) and haptoglobin, and stimulates that of a 2 -macroglobu-protein. 4 The HGF is active in primary cultured adult lin (AMG), which in man is insensitive to inflammatory rat hepatocytes 5 and, as shown recently, is also a potent mediators. HGF had no effect on C-reactive protein proliferating factor for adult human hepatocytes in cul-(CRP) synthesis. These effects differ from those elicited ture. 6
by interleukin-6 (IL-6). The effects of HGF on fibrinogenHuman HGF is thought to trigger in vivo liver regenand a 1 -antitrypsin were, however, similar to those in-eration. 7,8 It markedly increases in plasma following duced by IL-6. The effects of HGF were also observed at insults that stimulate liver regeneration (fulminant hethe messenger RNA (mRNA) level. Time-course induc-patic failure, toxic hepatitis, partial hepatectomy) [9][10][11] tion experiments showed that the effects of HGF on proand in the course of cirrhosis. 12 HGF production is detein synthesis were delayed by about 48 to 72 hours, in tected in nonparenchymal liver cells (Kupffer and sinucontrast with the 12-hour lag found after IL-6 stimulation. Although the presence of glucocorticoids was not soidal endothelial cells, 7,13,14 in fibroblasts, 15 and in absolutely necessary for HGF to affect plasma protein other distal organs such as the lung and kidney. 7,16,17 synthesis, it moderately extended the effects. In pulse-Until recently, HGF was considered essentially a mitochase experiments, it was found that the action of HGF gen for hepatocytes. Recent experimental evidence inwas not due to an alteration of the rate of secretion of the dicates, however, that HGF can act as a pleiotropic proteins. The effects of HGF on the synthesis of albumin, factor in different cells. 18,19 Thus, it could be also contransferrin, fibronectin, a 1 -antichymotrypsin, and hap-ceivable that HGF, in addition to acting as a potent toglobin could be counteracted by the simultaneous mitogen for human hepatocytes, might also influence
of HGF on human hepatocytes may not simply be limitedIn this study, we investigated the effects of HGF on to its mitogenic activity, but that it also regulates he-the synthesis of plasma proteins by human hepatocytes...