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 UP-REGULATION OF ENDOTHELIN-B RECEPTORS

During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype, proliferate, and synthetize f ibrosis components. We have shown that endothelin-1 (ET-1) inhibits th e proliferation of activated human HSC via endothelin B (ETB) receptor s. We now investigate the transduction pathway involved in the growth inhibitory effect of ET-1 in activated HSC. Endothelin-1 and the ETB r eceptor 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 in hibitory effect of ET-1. Analysis of early steps associated with growt h inhibition indicated that: (a) similar to ET-1, forskolin decreased c-jun mRNA induction without affecting c-fos and krox 24 mRNA expressi on; (b) ET-1, sarafotoxin-S6C, as well as forskolin, reduced activatio n of both c-Jun kinase and extracellular signal-regulated kinase. Fina lly, forskolin, PGI2, and PGE2 raised by fivefold the number of ET bin ding sites after 6 h, and increased the proportion of ETB receptors fr om 50% in control cells to 80% in treated cells. In conclusion, ET-1 i nhibits proliferation of activated HSC via ETB receptors, through a pr ostaglandin/cAMP pathway that leads to inhibition of both extracellula r signal-regulated kinase and c-Jun kinase activities. Upregulation of ETB receptors by prostaglandin/cAMP raises the possibility of a posit ive feedback loop that would amplify the growth inhibitory response. T hese results suggest that ET-1 and agents that increase cAMP might be of interest to limit proliferation of activated HSC during chronic liv er diseases.