Transforming growth factor beta1 helps maintain differentiated functions in mitogen-treated primary rat hepatocyte cultures.
Mechanisms that control function and repair of the injured liver remain unclear. We hypothesized that after liver injury, elevated blood TGF-beta1 levels may reflect an adaptive response to help maintain differentiated functions in surviving hepatocytes affected by excessive amounts of HGF. We thus studied the effect of HGF, EGF, TGF-beta1, HGF + TGF-beta1, or EGF + TGF-beta1 on the expression of liver-enriched transcription factors and genes which remain under their regulatory activity. The peak [3H]thymidine uptake induced by 20 ng/ml of either HGF or EGF was seen after 72 h; however, DNA binding of C/EBP and HNF1 decreased already after 6 h (electrophoretic mobility shift assay). Addition of TGF-beta1 antagonized these effects. Also at the mRNA level, TGF-beta1 counteracted at one point or another the decrease in C/EBPalpha, C/EBPbeta, HNF1beta, and HNF4 expression; HNF1alpha and COUP-TF showed similar responses and, additionally, were downregulated by TGF-beta1 at 24 h (Northern blot). Albumin and apolipoprotein B mRNA levels were decreased after 24-h treatment with HGF, whereas addition of TGF-beta1 increased their levels. The same pattern was found with EGF, but not until 48 h. PEPCK mRNA was dramatically lowered with either EGF or HGF, and TGF-beta1 did not counteract these effects. Id-1 was expressed only in cultures treated for 24 and 48 h with both the mitogen (EGF, HGF) and TGF-beta1 and in those treated for 48 h with TGF-beta1 alone.
Lilja
H
H
Department of Surgery, Burns and Allen Research Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA.
Kamohara
Y
Y
Neuman
T
T
Demetriou
A A
AA
Rozga
J
J
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology*
D008934:Mitogens; D016212:Transforming Growth Factor beta