THE HEPATOCYTE GROWTH-FACTOR REGULATES THE SYNTHESIS OF ACUTE-PHASE PROTEINS IN HUMAN HEPATOCYTES - DIVERGENT EFFECT ON INTERLEUKIN-6-STIMULATED GENES

Our study addressed the role of the human hepatocyte growth factor (HG F), a potent mitogen for mature rat and human hepatocytes, in the regu lation of specific hepatic genes. The experimental evidence obtained i n primary cultured human hepatocytes indicates that HGF regulates the synthesis of plasma proteins in a dose-response fashion. It stimulates the synthesis of the negative acute-phase proteins albumin, transferr in, and fibronectin, decreases that of alpha(1)-antichymotrypsin (ACT) and haptoglobin, and stimulates that of alpha(2)-macroglobulin (AMG), which in man is insensitive to inflammatory mediators. HGF had no eff ect on C-reactive protein (CRP) synthesis. These effects differ from t hose elicited by interleukin-6 (IL-6), The effects of HGF on fibrinoge n and alpha(1)-antitrypsin were, however, similar to those induced by IL-6. The effects of HGF were also observed at the messenger RNA (mRNA ) level, Time-course induction experiments showed that the effects of HGF on protein synthesis were delayed by about 48 to 72 hours, in cont rast with the 12-hour lag found after IL-6 stimulation, Although the p resence of glucocorticoids was not absolutely necessary for HGF to aff ect plasma protein synthesis, it moderately extended the effects. In p ulse-chase experiments, it was found that the action of HGF was not du e to an alteration of the rate of secretion of the proteins, The effec ts of HGF on the synthesis of albumin, transferrin, fibronectin, alpha (1)-antichymotrypsin, and haptoglobin could be counteracted by the sim ultaneous presence of IL-6 in the incubation media. A clear additive e ffect was observed only in the case of fibrinogen. No interaction was observed in the cases of CRP and AMG. The results of this study indica te that the effects of HGF on human hepatocytes may not simply be limi ted to its mitogenic activity, but that it also regulates hepatic-spec ific genes and antagonizes, in part, the action of IL-6.