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Am J Pathol. 2016 Jul;186(7):1874-1889. doi: 10.1016/j.ajpath.2016.03.010. Epub 2016 May 10.

Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression.

Author information

1
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
2
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Centre, RC Leiden, the Netherlands.
3
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
4
Division of Vascular Oncology and Metastasis, German Cancer Research Center, Center of Molecular Biology, Heidelberg University Alliance, Heidelberg, Germany.
5
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
6
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
7
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Division of Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
8
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
9
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
10
Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University, Magdeburg, Germany.
11
Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
12
Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Centre, RC Leiden, the Netherlands.
13
Division of Vascular Oncology and Metastasis, German Cancer Research Center, Center of Molecular Biology, Heidelberg University Alliance, Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; German Cancer Consortium, Heidelberg, Germany.
14
Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
15
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: zlym@zju.edu.cn.
16
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: honglei.weng@medma.uni-heidelberg.de.

Abstract

Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride- and bile duct ligation-challenged mouse models in vivo and evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4) ameliorated hepatocyte apoptosis, inflammation, and fibrosis in mice after carbon tetrachloride challenge. In vitro, rDll4 significantly decreased lipopolysaccharide-dependent chemokine expression in both Kupffer and hepatic stellate cells. In bile duct ligation mice, rDll4 induced massive hepatic necrosis, resulting in the death of all animals within 1 week. Inflammatory cell infiltration and chemokine ligand 2 (Ccl2) expression were significantly reduced in rDll4-receiving bile duct ligation mice. Recombinant Ccl2 rescued bile duct ligation mice from rDll4-mediated death. In patients with acute-on-chronic liver failure, DLL4 expression was inversely associated with CCL2 abundance. Mechanistically, Dll4 regulated Ccl2 expression via NF-κB. Taken together, Dll4 modulates liver inflammatory response by down-regulating chemokine expression. rDll4 application results in opposing outcomes in two models of liver damage. Loss of DLL4 may be associated with CCL2-mediated cytokine storm in patients with acute-on-chronic liver failure.

PMID:
27171900
PMCID:
PMC4929401
DOI:
10.1016/j.ajpath.2016.03.010
[Indexed for MEDLINE]
Free PMC Article

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