A synthetic peptide from transforming growth factor beta type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury.
Transforming growth factor beta1 (TGF-beta1) is a pleiotropic cytokine, which displays potent profibrogenic effects and is highly expressed in fibrotic livers. For this reason, development of TGF-B1 inhibitors might be of great importance to control liver fibrogenesis as well as other undesired side effects due to this cytokine. Potential peptide inhibitors of TGF-beta1 (derived from TGF-beta1 and from its type III receptor) were tested in vitro and in vivo using different assays. Peptides P11 and P12, derived from TGF-beta1, and P54 and P144, derived from its type III receptor, prevented TGF-beta1-dependent inhibition of MV1Lu proliferation in vitro and markedly reduced binding of TGF-beta1 to its receptors. P144 blocked TGF-beta1-dependent stimulation of a reporter gene under the control of human alpha2(I) collagen promoter. Intraperitoneal administration of P144 also showed potent antifibrogenic activity in vivo in the liver of rats receiving CCl4. These rats also showed a significant decrease in the number of activated hepatic stellate cells as compared with those treated with saline only. These results suggest that short synthetic peptides derived from TGF-beta1 type III receptor may be of value in reducing liver fibrosis in chronic liver injury.
Ezquerro
Ignacio-José
IJ
Departamento de Medicina Interna, Universidad de Navarra, Pamplona, Spain.
Lasarte
Juan-José
JJ
Dotor
Javier
J
Castilla-Cortázar
Inma
I
Bustos
Matilde
M
Peñuelas
Iván
I
Blanco
Gemma
G
Rodríguez
Carlos
C
Lechuga
Maria del Carmen G
Mdel C
Greenwel
Patricia
P
Rojkind
Marcos
M
Prieto
Jesús
J
Borrás-Cuesta
Francisco
F
D000595:Amino Acid Sequence; D000818:Animals; D002251:Carbon Tetrachloride; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011509:Proteoglycans / Q000737:chemistry*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry*; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1
D010455:Peptides; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C071736:betaglycan; D002251:Carbon Tetrachloride