Mallat A, Préaux A M, Serradeil-Le Gal C, Raufaste D, Gallois C, Brenner D A, Bradham C, Maclouf J, Iourgenko V, Fouassier L, Dhumeaux D, Mavier P, Lotersztajn S
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 99, Hôpital Henri Mondor, Créteil, France.
J Clin Invest. 1996 Dec 15;98(12):2771-8. doi: 10.1172/JCI119103.
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.
在慢性肝病过程中，肝星状细胞（HSC）获得活化的肌成纤维细胞样表型，增殖并合成纤维化成分。我们已经表明，内皮素-1（ET-1）通过内皮素B（ETB）受体抑制活化的人HSC的增殖。我们现在研究参与ET-1对活化HSC生长抑制作用的转导途径。内皮素-1和ETB受体激动剂萨拉毒素-S6C增加了PGI2和PGE2的合成，导致cAMP升高。环氧化酶抑制剂布洛芬和腺苷酸环化酶抑制剂SQ22536均减弱了ET-1的生长抑制作用。对与生长抑制相关的早期步骤的分析表明：（a）与ET-1相似，福斯高林降低了c-jun mRNA的诱导，而不影响c-fos和krox 24 mRNA的表达；（b）ET-1、萨拉毒素-S6C以及福斯高林均降低了c-Jun激酶和细胞外信号调节激酶的活化。最后，福斯高林、PGI2和PGE2在6小时后使ET结合位点的数量增加了五倍，并使ETB受体的比例从对照细胞中的50%增加到处理细胞中的80%。总之，ET-1通过ETB受体，通过前列腺素/cAMP途径抑制活化HSC的增殖，该途径导致细胞外信号调节激酶和c-Jun激酶活性均受到抑制。前列腺素/cAMP对ETB受体的上调增加了正反馈回路的可能性，该回路将放大生长抑制反应。这些结果表明，ET-1和增加cAMP的药物可能有助于限制慢性肝病期间活化HSC的增殖。
