Suppression of transforming growth factor-beta results in upregulation of transcription of regeneration factors after chronic liver injury.
OBJECTIVE
To determine the effects of dominant-negative TGF-beta receptor expression during liver regeneration in rats with dimethylnitrosamine (DMN)-induced liver injury.


METHODS
Rats were first treated with DMN for 3 weeks, and then intravenously injected once with AdTbeta-TR, AdLacZ, or saline. Serial changes in hepatocyte proliferation and apoptosis were evaluated by immunohistochemistry using anti-Ki67 antibody, and TUNEL staining, respectively. The mRNA expression of regeneration factors (HGF, TGF-alpha, EGF, and IGF-I) and IL-6 were evaluated by real-time PCR and northern blotting.


RESULTS
Anti-TGF-beta molecular intervention up-regulated hepatocyte proliferation and inhibited apoptosis. In the AdTbeta-TR-treated rats, EGF and IGF-I mRNA expression levels were significantly increased at day 1 and remained high for 3 days after gene transfer; TGF-alpha mRNA expression levels were significantly increased at 2 to 5 days after gene transfer; HGF mRNA expression levels were significantly up-regulated at day 2 only after gene transfer; while IL-6 mRNA expression level tended to increase at day 1, but decreased thereafter.


CONCLUSIONS
In rats with DMN-induced liver injury, anti-TGF-beta molecular intervention therapy stimulates proliferation and reduces apoptosis of hepatocytes, and also up-regulates the transcription of various growth factors.
Nakamura
Toru
T
Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume 830-0011, Japan.
Ueno
Takato
T
Sakamoto
Masaharu
M
Sakata
Ryuichiro
R
Torimura
Takuji
T
Hashimoto
Osamu
O
Ueno
Hikaru
H
Sata
Michio
M
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D002455:Cell Division; D056486:Chemical and Drug Induced Liver Injury; D002908:Chronic Disease; D004128:Dimethylnitrosamine; D018014:Gene Transfer Techniques; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration / Q000235:genetics; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015854:Up-Regulation
D006133:Growth Substances; D015850:Interleukin-6; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004128:Dimethylnitrosamine