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Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice

Donthamsetty, S and Mars, WM and Orr, A and Wu, C and Michalopoulos, GK (2011) Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice. Comparative Hepatology, 10.

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Background: Programmed cell death or apoptosis is an essential process for tissue homeostasis. Hepatocyte apoptosis is a common mechanism to many forms of liver disease. This study was undertaken to test the role of ILK in hepatocyte survival and response to injury using a Jo-2-induced apoptosis model.Methods: For survival experiments, ILK KO and WT mice received a single intraperitoneal injection of the agonistic anti-Fas monoclonal antibody Jo-2 at the lethal dose (0.4 μg/g body weight) or sublethal dose (0.16 μg/g body weight). For further mechanistic studies sublethal dose of Fas monoclonal antibody was chosen.Results: There was 100% mortality in the WT mice as compared to 50% in the KO mice. We also found that hepatocyte specific ILK KO mice (integrin linked kinase) died much later than WT mice after challenge with a lethal dose of Fas agonist Jo-2. At sublethal dose of Jo-2, there was 20% mortality in KO mice with minimal apoptosis whereas WT mice developed extensive apoptosis and liver injury leading to 70% mortality due to liver failure at 12 h. Proteins known to be associated with cell survival/death were differentially expressed in the 2 groups. In ILK KO mice there was downregulation of proapoptotic genes and upregulation of antiapoptotic genes.Conclusions: Mechanistic insights revealed that pro-survival pathways such as Akt, ERK1/2, and NFkB signaling were upregulated in the ILK KO mice. Inhibition of only NFkB and ERK1/2 signaling led to an increase in the susceptibility of ILK KO hepatocytes to Jo-2-induced apoptosis. These studies suggest that ILK elimination from hepatocytes protects against Jo-2 induced apoptosis by upregulating survival pathways. FAK decrease may also play a role in this process. The results presented show that the signaling effects of ILK related to these functions are mediated in part mediated through NFkB and ERK1/2 signaling. © 2011 Donthamsetty et al; licensee BioMed Central Ltd.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Donthamsetty, S
Mars, WMwmars@pitt.eduWMARS
Orr, Aavo4@pitt.eduAVO4
Wu, Ccarywu@pitt.eduCARYWU
Michalopoulos, GKmichal@pitt.eduMICHAL
Date: 21 November 2011
Date Type: Publication
Journal or Publication Title: Comparative Hepatology
Volume: 10
DOI or Unique Handle: 10.1186/1476-5926-10-11
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Date Deposited: 26 Oct 2016 18:04
Last Modified: 17 Oct 2017 19:55


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