Dokument: Inactive Rhomboid Protease 2 Reduces Liver Fibrosis by Inhibiting Proliferation of Hepatic Stellate Cells
| Titel: | Inactive Rhomboid Protease 2 Reduces Liver Fibrosis by Inhibiting Proliferation of Hepatic Stellate Cells | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=52639 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20200407-152155-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | M.Sc Sundaram, Balamurugan [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Lang, Philipp A. [Gutachter] Prof. Dr. Schmitt, Lutz [Gutachter] | |||||||
| Stichwörter: | Inactive Rhomboid Protease 2 Reduces Liver Fibrosis by Inhibiting Proliferation of Hepatic Stellate Cells | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for maturation of A disintegrin and
metalloprotease 17 (ADAM17, also called TACE), which is responsible for cleavage of membrane bound tumor necrosis factor α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we show that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice following BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2-/-) compared to controls. In vitro, primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo, TNFR shedding following BDL also depended on iRhom2. Treatment of Rhbdf2-/- mice with the TNF- α inhibitor Etanercept reduced the presence of stellate cells and alleviated liver fibrosis following BDL. Taken together, these data indicate that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Molekulare Medizin | |||||||
| Dokument erstellt am: | 07.04.2020 | |||||||
| Dateien geändert am: | 07.04.2020 | |||||||
| Promotionsantrag am: | 22.01.2020 | |||||||
| Datum der Promotion: | 27.02.2020 |
