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000130557 0247_ $$2doi$$a10.1016/j.ajpath.2016.03.010
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000130557 037__ $$aDKFZ-2017-05636
000130557 041__ $$aeng
000130557 082__ $$a610
000130557 1001_ $$aShen, Zhe$$b0
000130557 245__ $$aDelta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression.
000130557 260__ $$aNew York [u.a.]$$bElsevier$$c2016
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000130557 520__ $$aDisrupting 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.
000130557 536__ $$0G:(DE-HGF)POF3-311$$a311 - Signalling pathways, cell and tumor biology (POF3-311)$$cPOF3-311$$fPOF III$$x0
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000130557 650_7 $$2NLM Chemicals$$aChemokine CCL2
000130557 650_7 $$2NLM Chemicals$$aChemokines
000130557 650_7 $$2NLM Chemicals$$aIntracellular Signaling Peptides and Proteins
000130557 650_7 $$2NLM Chemicals$$aMembrane Proteins
000130557 650_7 $$2NLM Chemicals$$adelta protein
000130557 7001_ $$aLiu, Yan$$b1
000130557 7001_ $$aDewidar, Bedair$$b2
000130557 7001_ $$aHu, Junhao$$b3
000130557 7001_ $$aPark, Ogyi$$b4
000130557 7001_ $$aFeng, Teng$$b5
000130557 7001_ $$aXu, Chengfu$$b6
000130557 7001_ $$aYu, Chaohui$$b7
000130557 7001_ $$aLi, Qi$$b8
000130557 7001_ $$aMeyer, Christoph$$b9
000130557 7001_ $$aIlkavets, Iryna$$b10
000130557 7001_ $$aMüller, Alexandra$$b11
000130557 7001_ $$aStump-Guthier, Carolin$$b12
000130557 7001_ $$aMunker, Stefan$$b13
000130557 7001_ $$aLiebe, Roman$$b14
000130557 7001_ $$aZimmer, Vincent$$b15
000130557 7001_ $$aLammert, Frank$$b16
000130557 7001_ $$aMertens, Peter R$$b17
000130557 7001_ $$aLi, Hai$$b18
000130557 7001_ $$aTen Dijke, Peter$$b19
000130557 7001_ $$0P:(DE-He78)2e92d0ae281932fc7347d819fec36b0b$$aAugustin, Hellmut$$b20$$udkfz
000130557 7001_ $$aLi, Jun$$b21
000130557 7001_ $$aGao, Bin$$b22
000130557 7001_ $$aEbert, Matthias P$$b23
000130557 7001_ $$aDooley, Steven$$b24
000130557 7001_ $$aLi, Youming$$b25
000130557 7001_ $$aWeng, Hong-Lei$$b26
000130557 773__ $$0PERI:(DE-600)1480207-7$$a10.1016/j.ajpath.2016.03.010$$gVol. 186, no. 7, p. 1874 - 1889$$n7$$p1874 - 1889$$tThe American journal of pathology$$v186$$x0002-9440$$y2016
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