Z Gastroenterol 2012; 50 - K009
DOI: 10.1055/s-0032-1323944

Dll4 and Jagged-1 improve liver fibrosis dependent of etiology

Y Liu 1, 2, Z Shen 3, MY Xu 4, C Meyer 1, S Munker 1, Q Li 1, I Ilkavets 1, R Müllenbach 1, 5, P ten Dijke 2, J Li 4, S Dooley 1, LG Lu 4, Y Li 3, HL Weng 1
  • 1II. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim, Germany
  • 2Leiden University Medical Center, Department of Molecular Cell Biology and Center for Biomedical Genetics, RC Leiden, Netherlands
  • 3The First Affiliated Hospital, Zhejiang University School of Medicine, Department of Gastroenterology, Hangzhou, China
  • 4Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Department of Gastroenterology, Shanghai, China
  • 5Department of Medicine II, Saarland University Medical Center, Homburg, Germany

Background and aims: Humans have five Notch ligands (Jagged1, Jagged2, Delta like ligand (Dll)1, Dll3 and Dll4) and four receptors (Notch1, 2, 3 and 4). Mutation of Jagged-1 and Notch2 leads to Alagille syndrome, a disease characterized by defective development of intralobular bile ducts. Notch signaling drives hepatic progenitor cells differentiation into cholangiocytes during acute and chronic hepatic regeneration. It remains obscure whether Notch family proteins play a role in liver fibrosis. Here we investigated effects of Notch ligands in HBV-infected patients and experimental models.

Methods: Genechip analysis was used to investigate Notch associated genes in 7 healthy controls and 121 HBV infected patients with different fibrotic stages. Immunohistochemistry (IHC) was performed to detect expression of Notch ligands/receptors in liver tissue specimens from HBV patients. In vitro, we examined effects of Notch ligands in primary rat hepatic stellate cells (HSCs) and CFSC cell line. Finally, we investigated whether recombinant Notch ligands influence liver fibrosis in mice treated with carbon tetrachloride (CCl4) and common bile duct ligation (BDL).

Results: Microarray analyses revealed nine Notch signaling associated genes, e.g. Jagged-1, associated with fibrotic stages in HBV patients. IHC co-staining and confocal microscopy analyses identified that Jagged1, Dll4 and Notch1 localised in activated HSC and myofibroblasts, the main collagen producing liver cells, in HBV patients. Dll4 IHC score correlated with the inflammatory grade and fibrotic stage in these patients. In vitro, recombinant Jagged1 and Dll4 proteins significantly decreased TGF-b1 dependent mRNA expression of collagen I in HSCs. In mice treated with four weeks of CCl4, both recombinant Jagged-1 and Dll4 protein injection remarkably decreased serum ALT levels, liver inflammation and fibrosis. Interestingly, either recombinant Jagged-1 or Dll4 protein treatment caused death of experimental mice within three days after BDL operation.

Conclusions: Notch family proteins participate in liver fibrosis. The role of Notch ligands in liver fibrogenesis is etiology dependent. Recombinant Dll4 and Jagged-1 might be anti-fibrotic candidates for patients with liver fibrosis.