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: 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.
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Authors | Shashikiran Donthamsetty, Wendy M Mars, Anne Orr, Chuanyue Wu, George K Michalopoulos |
Journal | Comparative hepatology
(Comp Hepatol)
Vol. 10
Pg. 11
(Nov 21 2011)
ISSN: 1476-5926 [Electronic] England |
PMID | 22104495
(Publication Type: Journal Article)
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