TY - JOUR
T1 - Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression
AU - Shen, Zhe
AU - Liu, Yan
AU - Dewidar, Bedair
AU - Hu, Junhao
AU - Park, Ogyi
AU - Feng, Teng
AU - Xu, Chengfu
AU - Yu, Chaohui
AU - Li, Qi
AU - Meyer, Christoph
AU - Ilkavets, Iryna
AU - Müller, Alexandra
AU - Stump-Guthier, Carolin
AU - Munker, Stefan
AU - Liebe, Roman
AU - Zimmer, Vincent
AU - Lammert, Frank
AU - Mertens, Peter R.
AU - Li, Hai
AU - ten Dijke, Peter
AU - Augustin, Hellmut G.
AU - Li, Jun
AU - Gao, Bin
AU - Ebert, Matthias P.
AU - Dooley, Steven
AU - Li, Youming
AU - Weng, Hong Lei
N1 - Funding Information:
Supported by the Returned Overseas Chinese Scholars, State Education Ministry (Starting Research Foundation for the Returned Overseas Chinese Scholars, J20050337491010-G50523), People's Republic of China (H.-L.W.), Federal Ministry of Education and Research Virtual Liver and FP7 Marie Curie International Initial Training Networks in the Liver (P.t.D. and S.D.), SFB854/TP01, Me1365/7-2 and 9-1 (P.R.M.), Germany/China (German Academic Exchange Service — China Scholarship Council) Joint Research Program 2010/2011 (Z.S., C.X., Y.Li, C.M., S.D.), the intramural program of National Institute on Alcohol Abuse and Alcoholism, NIH (B.G.), the National Key Basic Research and Development Program of China-973 Program (2012CB524905; Y.Li), National Science and technology support program of China (2012BAI06B04; Y.Li), Zhejiang provincial laboratory animal science and technology program of China (2011C37088; Z.S.), German Egyptian Research Long-Term Scholarship of DAAD/Egypt government (B.D.), and Federal Ministry of Education and Research – Virtual Liver Network (S.D.).
Publisher Copyright:
© 2016 American Society for Investigative Pathology
PY - 2016/7
Y1 - 2016/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2016.03.010
DO - 10.1016/j.ajpath.2016.03.010
M3 - Article
C2 - 27171900
AN - SCOPUS:84997335638
SN - 0002-9440
VL - 186
SP - 1874
EP - 1889
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 7
ER -