%0 Journal Article
%T Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice
%A Shashikiran Donthamsetty
%A Wendy M Mars
%A Anne Orr
%A Chuanyue Wu
%A George K Michalopoulos
%J Comparative Hepatology
%D 2011
%I BioMed Central
%R 10.1186/1476-5926-10-11
%X 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 ¦Ìg/g body weight) or sublethal dose (0.16 ¦Ìg/g body weight). For further mechanistic studies sublethal dose of Fas monoclonal antibody was chosen.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.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.Programmed cell death or apoptosis is an essential process for tissue homeostasis. Hepatocyte apoptosis is a common mechanism to many forms of liver disease. It has been recognized to contribute to the pathogenesis of alcoholic liver disease, nonalcoholic steatohepatitis, viral hepatitis, cholestatic liver disease, and ischemia/reperfusion injury [1-4]. Apoptosis can be triggered by Fas receptor mediated signaling as well as different
%K Integrin linked kinase
%K Jo-2
%K Apoptosis
%K ECM signaling
%U http://www.comparative-hepatology.com/content/10/1/11