Insulin-like growth factor (IGF)-binding protein-1 is highly induced during acute carbon tetrachloride liver injury and potentiates the IGF-I-stimulated activation of rat hepatic stellate cells.
Hepatic stellate cells (HSC) play a pivotal role in hepatic tissue repair and fibrogenesis. IGF-I has been considered a mitogenic signal for activation and proliferation of HSC in vitro. In the present study IGF-I and IGF-binding protein (IGFBP) gene expression was studied in a model of acute liver injury induced by a single intragastric dose of carbon tetrachloride (CCl(4)) in adult rats. Northern blot analysis revealed a marked increase in IGFBP-1 mRNA levels, with a maximum between 3 and 9 h after CCl(4) application, whereas steady state mRNA levels of IGF-I were only moderately altered. In situ hybridization experiments demonstrated that this increase in IGFBP-1 mRNA was due to a strong expression of IGFBP-1 in the perivenous region 6-12 h after CCl(4) application, extending to the midzonal region of the acinus within 24-48 h. Consequently, a prominent immunostaining for IGFBP-1 was observed in perivenous areas, with a maximum 24-48 h after intoxication. Preincubation of early cultured HSC with a nonphosphorylated IGFBP-1 from human amniotic fluid resulted in a 3.4-fold increase in IGF-I-induced DNA synthesis. The mitogenic effect of IGF-I was also potentiated when HSC were cocultivated with IGFBP-1-overexpressing BHK-21 cells compared with nontransfected cells. These data suggest that IGFBP-1 released during the early steps of liver tissue damage and repair may interact with HSC and potentiate the sensitivity of IGF-I to mitogenic signals.
Scharf
Jens-Gerd
JG
Department of Medicine, University of Göttingen, Germany.
Dombrowski
Frank
F
Novosyadlyy
Ruslan
R
Eisenbach
Christoph
C
Demori
Ilaria
I
Kübler
Bernd
B
Braulke
Thomas
T
D000208:Acute Disease; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000502:physiology; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I; D004247:DNA