INSULIN-LIKE GROWTH-FACTORS STIMULATE EXPRESSION OF HEPATOCYTE GROWTH-FACTOR BUT NOT TRANSFORMING-GROWTH-FACTOR BETA(1) IN CULTURED HEPATICSTELLATE CELLS

Hepatic stellate cells (HSC) are located adjacent to hepatocytes and p roduce hepatocyte growth factor (HGF) in the normal liver, whereas tra nsformed HSC in fibrotic livers produce transforming growth fac tor be ta(1) (TGF beta(1)), an inhibitor of hepatocyte proliferation. In addi tion to the endocrine actions of hepatic insulin-like growth factor-1 (IGF-1), it also stimulates the proliferation of HSC. In this study we found that addition of IGF-1 (20-500 ng/ml) for 48 h to 2- to 7-day-o ld primary cultures of rat HSC resulted in a time-and dose-dependent i ncrease by 50-190% of the concentrations of immunoreactive HGF in the medium. The levels of HGF as well as DNA synthesis measured as thymidi ne incorporation were also enhanced by IGF-II and des(1-3)IGF-I,which has reduced binding to IGF binding proteins. There was no consistent e ffect of the IGFs on the levels of immunoreactive TGF beta(1), or on t he total DNA content of the cultures. There was no effect of human GH on medium levels of HGF or TGF beta(1), thymidine incorporation, or to tal DNA content. IGF-1 increased the abundance of HGF messenger RNA, a s measured by the RNase protection/solution hybridization technique, w hereas there was no effect on TGF beta(1), or glyceraldehyde phosphate dehydrogenase messenger RNA. The results suggest that IGFs stimulate the production of HGF but not TGF beta(1), by HSC in vitro.