title: Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice.
abstract: 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.
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. michalopoulosgk@upmc.edu.
authors: Shashikiran
authors: S
authors: Donthamsetty
authors: Wendy M
authors: WM
authors: Mars
authors: Anne
authors: A
authors: Orr
authors: Chuanyue
authors: C
authors: Wu
authors: George K
authors: GK
authors: Michalopoulos