PRODUCTION OF INSULIN-LIKE GROWTH-FACTORS AND THEIR BINDING-PROTEINS IN PRIMARY CULTURES OF RAT-LIVER PARENCHYMAL AND NONPARENCHYMAL CELLS

Regulation of the production of insulin-like growth factor (IGF)-I, IG F-II, IGF binding proteins (IGFBPs), and their related proteins by var ious hormones was investigated in primary cultures of rat liver parenc hymal and nonparenchymal cells. Freshly isolated parenchymal cells con tained mRNAs of IGF-I, IGF-II, IGFBP-1, IGFBP-4, growth hormone (GH) r eceptor, and the acid-labile subunit (ALS), which forms a ternary comp lex with IGF-I and IGFBP-3; however, parenchymal cells did not express the IGFBP-3 gene. In contrast, nonparenchymal cells contained IGFBP-3 mRNA exclusively, as we reported previously [Takenaka ct al. Agric. B iol. Chem., 55, 1191-1193 (1991)]. Cultured rat parenchymal cells prod uced IGF-I, IGFBP-1, and IGFBP-4 prominently. In these cells, secretio n of IGF-I and the content of IGF-I mRNA was greatly increased in the presence of GH in the medium. Insulin also increased the production of IGF-I. Secretion of IGFBP-1 into the medium was enhanced by treatment with glucagon, dibutyrylcyclic AMP (Bu(2)cAMP), and dexamethasone (De x) and these enhancements with glucagon and Dex reflected the increase in its mRNA content. Insulin depressed the secretion of IGFBP-1. The content of IGFBP-4 in the parenchymal cells was increased by insulin, Bu(2)cAMP, and triiodothyronine (T-3), thereby enhancing the productio n of IGFBP-4 and secretion into the medium. Cultured liver nonparenchy mal cells of rats produced IGFBP-1, IGFBP-3, and IGFBP-4. Secretion of IGFBP-1 was increased by Bu(2)cAMP in the medium, that of IGFBP-3 by IGF-I, and that of IGFBP-4 by both IGF-I and Bu(2)cAMP. Regulation of the production of IGFBP-3 by IGF-I was demonstrated in these investiga tions. These results suggest that GH increases production of IGF-I in the parenchymal cells and this IGF-I, in turn, increases the productio n of IGFBP-3 in nonparenchymal cells. As we found GH also increases AL S production in parenchymal cells, by these mechanisms, GH increases t he formation of the ternary complex of IGF-I, IGFBP-3, and ALS. This s tudy clearly demonstrates the interrelationship between parenchymal an d nonparenchymal cells in the production of IGF-I and IGFBPs in the li ver.