GROWTH-INHIBITORY PROPERTIES OF ENDOTHELIN-1 IN HUMAN HEPATIC MYOFIBROBLASTIC ITO CELLS - AN ENDOTHELIN-B RECEPTOR-MEDIATED PATHWAY

Ito cells play a pivotal role in the development of liver fibrosis ass ociated with chronic liver diseases. During this process, Ito cells ac quire myofibroblastic features, proliferate, and synthesize fibrosis c omponents, Considering the reported mitogenic properties of endothelin -1 (ET-1), we investigated its effects on the proliferation of human I to cells in their myofibroblastic phenotype. Both ET receptor A (ETA: 20%) and ET receptor B (ETB: 80%) binding sites were identified, using a selective ETA antagonist, BQ 123, and a selective ETB agonist, sara fotoxin S6C (SRTX-C). ET-1 did not stimulate proliferation of myofibro blastic Ito cells. In contrast, ET-1 inhibited by 60% DNA synthesis an d proliferation of cells stimulated with either human serum or platele t-derived growth factor -BB (PDGF-BB), PD 142893, a nonselective ETA/E TB antagonist totally blunted this effect. SRTX-C was as potent as ET- 1, while BQ 123 did not affect ET-1-induced growth inhibition. Analysi s of the intermediate steps leading to growth-inhibition by ET-1 revea led that activation of mitogen-activated protein kinase by serum or PD GF-BB was decreased by 50% in the presence of SRTX-C. In serum-stimula ted cells, SRTX-C reduced c-jun mRNA expression by 50% whereas c-fos o r krox 24 mRNA expression were not affected. We conclude that ET-1 bin ding to ETB receptors causes a potent growth inhibition of human myofi broblastic Ito cells, which suggests that this peptide could play a ke y role in the negative control of liver fibrogenesis. Our results also point out that, in addition to its well known promitogenic effects, E T-1 may also exert negative control of growth on specific cells.