RGD Reference Report - Preproendothelin-1 expression is negatively regulated by IFNgamma during hepatic stellate cell activation. - Rat Genome Database

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Preproendothelin-1 expression is negatively regulated by IFNgamma during hepatic stellate cell activation.

Authors: Li, T  Shi, Z  Rockey, DC 
Citation: Li T, etal., Am J Physiol Gastrointest Liver Physiol. 2012 May 1;302(9):G948-57. doi: 10.1152/ajpgi.00359.2011. Epub 2012 Feb 2.
RGD ID: 8662301
Pubmed: PMID:22301113   (View Abstract at PubMed)
PMCID: PMC3362071   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpgi.00359.2011   (Journal Full-text)

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-gamma (IFNgamma), a Th1 cytokine produced by T cells, inhibits stellate cell proliferation, fibrogenesis, and muscle-specific gene expression. Whether IFNgamma-induced inhibitory effects are linked to regulation of ET-1 expression in activated stellate cells remains unknown. Here we examined IFNgamma'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; IFNgamma 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 IFNgamma. PreproET-1 promoter analysis revealed that IFNgamma-induced inhibition of preproET-1 mRNA expression was closely linked to the AP-1 and Smad3 signaling pathways. Furthermore, IFNgamma 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, IFNgamma 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 IFNgamma inhibits preproET-1 expression, highlighting one potential molecular mechanism for IFNgamma-induced host immunomodulation of liver fibrogenesis.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to type II interferon  IEP 8662301 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Edn1  (endothelin 1)


Additional Information