title: Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression.
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.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
authors.forename: Bedair
authors.initials: B
authors.lastname: Dewidar
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center, Center of Molecular Biology, Heidelberg University Alliance, Heidelberg, Germany.
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Teng
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chengfu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Ilkavets
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Müller
authors.affiliation: 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.
authors.forename: Carolin
authors.initials: C
authors.lastname: Stump-Guthier
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Munker
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Liebe
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zimmer
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.affiliation: Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.affiliation: Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Centre, RC Leiden, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: 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.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Ebert
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: zlym@zju.edu.cn.
authors.forename: Youming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: honglei.weng@medma.uni-heidelberg.de.
authors.forename: Hong-Lei
authors.initials: HL
authors.lastname: Weng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein