{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:49:18Z","timestamp":1773427758724,"version":"3.50.1"},"reference-count":36,"publisher":"American Physiological Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2012,5,1]]},"abstract":"<jats:p>Endothelin-1 (ET-1), a powerful vasoconstrictor peptide, is produced by activated hepatic stellate cells (HSC) and promotes cell proliferation, fibrogenesis, and contraction, the latter of which has been thought to be mechanistically linked to portal hypertension in cirrhosis. Interferon-\u03b3 (IFN\u03b3), a Th1 cytokine produced by T cells, inhibits stellate cell proliferation, fibrogenesis, and muscle-specific gene expression. Whether IFN\u03b3-induced inhibitory effects are linked to regulation of ET-1 expression in activated stellate cells remains unknown. Here we examined IFN\u03b3's effects on preproET-1 mRNA expression and the signaling pathways underlying this process. We demonstrated that preproET-1 mRNA expression in HSCs was prominently increased during cell culture-induced activation; IFN\u03b3 significantly inhibited both preproET-1 mRNA expression and ET-1 peptide production. Similar results were found in an in vivo model of liver injury and intraperitoneal administration of IFN\u03b3. PreproET-1 promoter analysis revealed that IFN\u03b3-induced inhibition of preproET-1 mRNA expression was closely linked to the AP-1 and Smad3 signaling pathways. Furthermore, IFN\u03b3 reduced JNK phosphorylation, which tightly was associated with decreased phosphorylation of downstream factors c-Jun and Smad3 and decreased binding activity of c-Jun and Smad3 in the preprpET-1 promoter. Importantly, IFN\u03b3 reduced both c-Jun mRNA and protein levels. Given the important role of ET-1 in wound healing, our results suggest a novel negative signaling network by which IFN\u03b3 inhibits preproET-1 expression, highlighting one potential molecular mechanism for IFN\u03b3-induced host immunomodulation of liver fibrogenesis.<\/jats:p>","DOI":"10.1152\/ajpgi.00359.2011","type":"journal-article","created":{"date-parts":[[2012,2,3]],"date-time":"2012-02-03T06:40:26Z","timestamp":1328251226000},"page":"G948-G957","source":"Crossref","is-referenced-by-count":24,"title":["Preproendothelin-1 expression is negatively regulated by IFN\u03b3 during hepatic stellate cell activation"],"prefix":"10.1152","volume":"302","author":[{"given":"Tianxia","family":"Li","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zengdun","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of 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