title: Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.
abstract: During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype, proliferate, and synthetize fibrosis components. We have shown that endothelin-1 (ET-1) inhibits the proliferation of activated human HSC via endothelin B (ETB) receptors. We now investigate the transduction pathway involved in the growth inhibitory effect of ET-1 in activated HSC. Endothelin-1 and the ETB receptor agonist, sarafotoxin-S6C, increased synthesis of PGI2 and PGE2, leading to elevation of cAMP. The cyclooxygenase inhibitor ibuprofen and the adenylyl cyclase inhibitor SQ22536 both blunted the growth inhibitory effect of ET-1. Analysis of early steps associated with growth inhibition indicated that: (a) similar to ET-1, forskolin decreased c-jun mRNA induction without affecting c-fos and krox 24 mRNA expression; (b) ET-1, sarafotoxin-S6C, as well as forskolin, reduced activation of both c-Jun kinase and extracellular signal-regulated kinase. Finally, forskolin, PGI2, and PGE2 raised by fivefold the number of ET binding sites after 6 h, and increased the proportion of ETB receptors from 50% in control cells to 80% in treated cells. In conclusion, ET-1 inhibits proliferation of activated HSC via ETB receptors, through a prostaglandin/cAMP pathway that leads to inhibition of both extracellular signal-regulated kinase and c-Jun kinase activities. Upregulation of ETB receptors by prostaglandin/cAMP raises the possibility of a positive feedback loop that would amplify the growth inhibitory response. These results suggest that ET-1 and agents that increase cAMP might be of interest to limit proliferation of activated HSC during chronic liver diseases.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 99, Hôpital Henri Mondor, Créteil, France.
authors.forename: A
authors.initials: A
authors.lastname: Mallat
authors.forename: A M
authors.initials: AM
authors.lastname: Préaux
authors.forename: C
authors.initials: C
authors.lastname: Serradeil-Le Gal
authors.forename: D
authors.initials: D
authors.lastname: Raufaste
authors.forename: C
authors.initials: C
authors.lastname: Gallois
authors.forename: D A
authors.initials: DA
authors.lastname: Brenner
authors.forename: C
authors.initials: C
authors.lastname: Bradham
authors.forename: J
authors.initials: J
authors.lastname: Maclouf
authors.forename: V
authors.initials: V
authors.lastname: Iourgenko
authors.forename: L
authors.initials: L
authors.lastname: Fouassier
authors.forename: D
authors.initials: D
authors.lastname: Dhumeaux
authors.forename: P
authors.initials: P
authors.lastname: Mavier
authors.forename: S
authors.initials: S
authors.lastname: Lotersztajn
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016758:Genes, jun / Q000235:genetics; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D011453:Prostaglandins; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; D005576:Colforsin; C026678:carboprostacyclin; D011464:Epoprostenol; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D007052:Ibuprofen