Pleiotrophin inhibits transforming growth factor beta1-induced apoptosis in hepatoma cell lines.
Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. In this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor beta1 (TGFbeta1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGFbeta1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGFbeta1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGFbeta1-reluctant cells. The TGFbeta1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGFbeta1 activity during liver fibrosis.
Park
Tae Jun
TJ
Biochemistry and Molecular biology, School of Medicine, Ajou University, Suwon, South Korea.
Jeong
Bo Ra
BR
Tateno
Chise
C
Kim
Hong Seok
HS
Ogawa
Tomohiro
T
Lim
In Kyoung
IK
Yoshizato
Katsutoshi
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology*; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D002352:Carrier Proteins; D016207:Cytokines; D053773:Transforming Growth Factor beta1; C066845:pleiotrophin