A blocking peptide for transforming growth factor-beta1 activation prevents hepatic fibrosis in vivo.
OBJECTIVE
Thrombospondin-1 is a major activator of transforming growth factor-beta1 (TGF-beta1), and a peptide derived from the latency-associated peptide, Leu-Ser-Lys-Leu (LSKL), inhibits the activation of TGF-beta1. In this study, the effects of LSKL on the hepatocyte damage and fibrogenesis in dimethylnitrosamine (DMN)-induced rat liver fibrosis were examined.


METHODS
Animals were given an intraperitoneal (i.p.) injection of DMN or saline three times per week for 4 weeks, and treated with LSKL, a control peptide, or saline i.p. daily.


RESULTS
Liver atrophy caused by DMN-injection was significantly inhibited in the DMN+LSKL group. The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the DMN+LSKL group than in the control groups. The hydroxyproline content was significantly higher in the control groups than in the DMN+LSKL group. The amount of active TGF-beta1 was less in the DMN+LSKL group than in the control groups, and the active/total TGF-beta1 ratio in the DMN+LSKL group was suppressed in the control groups. Phosphorylation of Smad 2 in the liver was significantly decreased in the DMN+LSKL group.


CONCLUSIONS
The LSKL peptide prevented the progression of hepatic damage and fibrosis through the inhibition of TGF-beta1 activation and its signal transduction in vivo.
Department of Developmental Medicine (Pediatrics), D-5, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. hiroki@ped.med.osaka-u.ac.jp
Hiroki
H
Kondou
Sotaro
S
Mushiake
Yuri
Y
Etani
Yoko
Y
Miyoshi
Toshimi
T
Michigami
Keiichi
K
Ozono
D000818:Animals; D001284:Atrophy; D004268:DNA-Binding Proteins / Q000378:metabolism; D004128:Dimethylnitrosamine; D018450:Disease Progression; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009336:Necrosis; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; C487834:Leu-Ser-Lys-Leu peptide; D010455:Peptides; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004128:Dimethylnitrosamine; D006909:Hydroxyproline