The liver is very sensitive to Fas-induced apoptosis. Administration anti-Fas agonistic antibody Cilengitide mw Jo-2 to mice leads to rapid death of the animals due to fulminant hepatitis, mimicking certain forms of acute liver failure (ALF) in humans [5]. Fas (CD95/APO-1), a 43-kDa cell surface glycoprotein, belongs to the tumor necrosis factor receptor superfamily, and mediates apoptosis upon binding with its cognate ligand, or artificially with specific agonistic antibodies. Communication between cells and the extracellular matrix (ECM) is achieved through integrins

and the associated integrin proximal adhesion molecules. Through multiple protein-protein interactions and signaling events, these molecules transmit signals from the ECM to the interior of the cell and regulate many fundamental cellular processes. learn more Integrin-linked kinase (ILK) is a β1- and β3-integrin-interacting cell matrix adhesion protein that has been shown to be crucial for a number of cellular processes such as survival, differentiation, proliferation, migration, and angiogenesis [6–8]. Previous studies selleck chemicals llc in our lab have shown that acute elimination of ILK by injection of adenovirus expressing Cre recombinase in the tail vein of ILKflox/flox mice led to massive hepatocyte apoptosis [9]. Genetic ablation of ILK also results in some degree of apoptosis

[10] but also to an enhancement of hepatocyte proliferation, suggesting that ILK might be playing a role in hepatocyte survival. This study was undertaken to test the role of ILK in hepatocyte survival and response to injury using a Jo-2-induced apoptosis model. Here we report that genetic ablation of ILK from hepatocytes protects from Jo-2 induced apoptosis due to upregulation of survival signaling mainly ERK and NFκB signaling. Methods Generation of liver specific ILK/liver-/- mice ILK floxed animals were generated as described previously [10] and donated by Drs. Proteasome inhibitor René St. Arnaud (Shriners Hospital and McGill University, Montréal) and Shoukat Deodhar (British Columbia Cancer Agency and Vancouver Hospital, Jack Bell Research Center, Vancouver),

and mated with AFP-enhancer-albumin-promoter-Cre-recombinase-expressing mice which were kindly provided by Dr. Klaus Kaestner (University of Pennsylvania). The off-spring were genotyped as described previously [11] and the ILK-floxed/floxed Cre-positive mice were considered to be ILK-knockout (ILK KO), while their Cre-negative siblings were used as controls. All animals were housed in the animal facility of the University of Pittsburgh in accordance with the guidelines of the Institutional Animal Use and Care Committee of the University of Pittsburgh. Induction of apoptosis For survival experiments, male 30 week-old ILK KO (n = 10) and control mice (n = 10) received a single intraperitoneal injection of the agonistic anti-Fas monoclonal antibody Jo-2 (BD Pharmingen, San Diego, CA) at the lethal dose (0.