Z Gastroenterol 2011; 49 - P1_58
DOI: 10.1055/s-0030-1269508

Jagged-1 signalling is required in liver fibrogensis

H Weng 1, Y Liu 2, I Ilkavets 2, H Shen 2, V Zimmer 3, F Lammert 3, A Mueller 2, F Herweck 2, C Stump 2, PR Mertens 4, S Dooley 1
  • 1Medizinische Fakultät Mannheim der Universität Heidelberg, II. Medizinische Klinik, Mannheim, Deutschland
  • 2Medizinische Klinik II; Universitätsmedizin Mannheim; Universität Heidelberg, Mannheim
  • 3Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany, Homburg
  • 4Department of Nephrology and Hypertension, Otto-von-Guericke-University, Magdeburg, Germany

Background & Aims: Mutation of Jagged-1 gene, a Notch ligand, leads to Alagille syndrome. However, patients with Alagille syndrome usually do not progress into serious liver fibrosis. In the present study, we investigated the role of Jagged-1 in liver fibrogenesis. Methods: Jagged-1 expression in diseased human and mouse livers were evaluated by immunohistochemistry and Western blot. The effect of a Jagged-1 was examined in hepatic stellate cells (HSCs). Results: Immunohistochemistry and Western blot analysis revealed that protein expression of Jagged-1 in liver tissues from 2-week bile duct ligated mice was significantly increased compared to sham operated mice. Consistently, enhanced Jagged-1 expression was found in 80 HBV and 65 HCV patients, when compared to 5 normal liver samples by immunohistochemistry. In vitro, a gamma-secretase inhibitor (GSI), representing a general inhibitor for Notch receptor signaling, markedly decreased TGF-beta induced mRNA expression of collagen I as well as protein expression of alpha-smooth muscle actin and connective tissue growth factor (CTGF) in rat HSCs. Furthermore, knock-down of Jagged-1 by using siRNA significantly decreased protein expression of collagen I and CTGF in CFSC cells, a cell line from CCl4-induced cirrhotic rat HSCs. Conclusions: Jagged-1 plays a crucial role in liver fibrogenesis possibly via influencing activation of HSCs and extracelluar matrix production.

CTGF - Hepatic stellate cell - Notch - alpha-smooth muscle actine - collagen