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.
OBJECTIVE
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-1beta and tumor necrosis factor alpha (TNFalpha) 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 [(125)I]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-1beta or TNFalpha 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.
Lelbach
A
A
Department of Medicine, Division of Gastroenterology and Endocrinology, Georg-August-Universität, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Scharf
J G
JG
Ramadori
G
G
D000818:Animals; D018920:Coculture Techniques; D015342:DNA Probes; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D007728:Kupffer Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects
D015342:DNA Probes; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D015850:Interleukin-6; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I