Regulation of insulin-like growth factor-I and of insulin-like growth factor binding protein-1,-3 and-4 in cocultures of rat hepatocytes and Kupffer cells by interleukin-6

Background/Aims: Catabolism is associated with decreased serum concentrations of insulin-like growth factor (IGF)I and insulin-like growth factor binding protein (IGFBP)-3 associated with elevated IGFBP-3 protease activity and increased concentrations of IGFBP-1 and -4. The effects of the acute phase mediators interleukin (IL)-6, IL-1 beta and tumor necrosis factor at (TNF alpha) on the biosynthesis of IGF-I and IGFBPs were studied in primary rat liver cells. Methods: mRNA levels of IGF-I and of IGFBPs were analyzed by Northern blotting, secretion of IGFBPs by [I-125]IGF-I ligand blotting. Proteolytic activity was measured using iodinated recombinant IGFBP-3 as the substrate. Results: In hepatocytes, Kupffer cells (KC) and cocultures of hepatocytes with KC, IL-6 reduced IGF-I biosynthesis dose-dependently. IL-6 stimulated mRNA expression and protein secretion of IGFBP-1 and -4 in hepatocytes and that of IGFBP-3 in KC, respectively. In cocultures, biosynthesis of IGFBP-1, -3 and -4 was increased dose-dependently by IL-6, while the effects of IL-1 beta or TNF alpha were less prominent. At neutral pH, proteolytic activity against IGFBP-3 was not detected in media of cocultures treated with IL-6. Conclusions: The alterations of IGF-I, IGFBP-1 and -4 observed in catabolism correlate with the effects of IL-6 on the biosynthesis of these components in primary rat liver cells, while a neutral IGFBP-3 protease was not detectable. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.