Journal Article

DKFZ-2017-05636

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression.

Shen, Z. ; Liu, Y. ; Dewidar, B. ; Hu, J. ; Park, O. ; Feng, T. ; Xu, C. ; Yu, C. ; Li, Q. ; Meyer, C. ; Ilkavets, I. ; Müller, A. ; Stump-Guthier, C. ; Munker, S. ; Liebe, R. ; Zimmer, V. ; Lammert, F. ; Mertens, P. R. ; Li, H. ; Ten Dijke, P. ; Augustin, H.DKFZ* ; Li, J. ; Gao, B. ; Ebert, M. P. ; Dooley, S. ; Li, Y. ; Weng, H.-L.

2016
Elsevier New York [u.a.]

This record in other databases:  

Please use a persistent id in citations: doi:10.1016/j.ajpath.2016.03.010

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.

Keyword(s): Chemokine CCL2 ; Chemokines ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; delta protein

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Contributing Institute(s):

1. Vaskuläre Onkologie und Metastasierung (A190)
2. DKTK Heidelberg (L101)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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