title: Tumor necrosis factor α stimulates endothelin-1 synthesis in rat hepatic stellate cells in hepatic wound healing through a novel IKK/JNK pathway.
abstract: Endothelin-1 (ET-1), a potent vasoconstrictor peptide up-regulated during wound healing and fibrosis, induces myofibroblasts to contract tissue. Here we have used a liver injury model to test the hypothesis that TNFα may be an important stimulator of ET-1 production in hepatic wound healing. We examined primary rat hepatic stellate cells, isolated from either normal or injured livers and used standard methodology to measure preproET-1 mRNA and mature ET-1 peptide, specific kinases, and preproET-1 promoter activity. Chromatin immunoprecipitation analysis was used to determine basal binding of transcription factors to the preproET-1 promoter. TNFα induced preproET-1 expression in activated hepatic stellate cells in a c-Jun N-terminal kinase (JNK)/AP-1-dependent fashion. TNFα activated JNK through an IκB kinase (IKK) pathway, which activated the transcriptional factor, c-Jun, leading to preproET-1 promoter mediated ET-1 transcription. The TNFα mediated induction of ET-1 synthesis also had functional effects, specifically mediating autocrine induced stellate cell contraction. TNFα stimulated activated stellate cells to produce ET-1 via a novel IKK-JNK-dependent signaling pathway. The resulting autocrine functional effects of ET-1 are likely to be important in the wound-healing process.
authors.affiliation: Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887, USA.
authors.forename: Shuxin
authors.initials: S
authors.lastname: Zhan
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000293:injuries; D008297:Male; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases