Antiproliferative effects of ET-1 in human liver Ito cells: an ETB- and a cyclic AMP-mediated pathway.
Ito cells play a key role in the development of liver fibrosis associated with chronic liver diseases. Both ETA (20%) and ETB (80%) receptors were identified in human Ito cells. ET-1 did not stimulate proliferation of Ito cells. In contrast, ET-1 inhibited DNA synthesis stimulated by serum or PDGF-BB, through an ETB-mediated pathway. The mechanism leading to growth inhibition involved elevation of cAMP leading to inhibition of serum-stimulated MAP kinase and selective reduction of c-jun expression. Finally, ET receptors were upregulated by cAMP, providing a positive feedback loop that would amplify ET-1-induced growth inhibition. We conclude that ET-1 is a potent growth inhibitory peptide and may exert positive or negative control of cell growth, depending on cell type. Moreover, this peptide may play a key role in the negative control of liver fibrogenesis.
Mallat
A
A
INSERM U99, Hôpital Henri Mondor, Crétiel, France.
Fouassier
L
L
Préaux
A M
AM
Mavier
P
P
Lotersztajn
S
S
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D016232:Endothelins / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000032:analysis / Q000502:physiology*; D014757:Viper Venoms / Q000494:pharmacology
D016232:Endothelins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; D005576:Colforsin; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases