Hypoxic conditions restore lost sensitivity to the growth inhibitory effect of transforming growth factor beta-1 (TGF beta-1) in proliferating rat hepatocytes in vitro.
TGF beta-1 is known to be a growth inhibitor of regenerating liver, and an inducer of hepatocyte apoptosis in primary culture. However, hepatocytes can proliferate after partial hepatectomy even at high serum TGF beta-1 concentrations. In this study we used the primary cultures of rat hepatocytes for 10 days to investigate how TGF beta-1 affects proliferating hepatocytes. DNA synthesis peaked on day 8 of culture, and TGF beta-1-induced apoptosis was significantly suppressed on day 8 compared to days 2, 5, and 10. Flow-cytometric analysis revealed that hepatocytes that had incorporated BrdU were resistant to the apoptotic effect of TGF beta-1, and Northern blot analysis showed that TGF beta receptor mRNA was down-regulated on day 8. Hypoxic conditions restores TGF beta receptor mRNA expression and the lost sensitivity of proliferating hepatocyte to TGF beta-1.
Kakihara
N
N
The First Department of Surgery, Shiga University of Medical Science Seta-tsukinowacho, Otsu-city, Japan. kakihara@belle.shiga-med.ac.jp
Takeshita
K
K
Ishibashi
H
H
Tani
T
T
Kodama
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D015536:Down-Regulation; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004247:DNA; D001973:Bromodeoxyuridine