concanavalin-a and Reperfusion-Injury

Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ1

Topics: Alanine Transaminase; Alarmins; Animals; Antibodies, Monoclonal; Aspartate Aminotransferases; Cell Adhesion Molecules, Neuronal; Cell Death; Cell Membrane; Concanavalin A; Galactosamine; Hepatocytes; Inflammation; Lactate Dehydrogenases; Liver; Mice; Microscopy, Electron; Nerve Growth Factors; Neutrophil Infiltration; Reperfusion Injury

The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.

Topics: Animals; Apoptosis; Cells, Cultured; Concanavalin A; Hepatocytes; I-kappa B Kinase; Liver; Male; Mice; Mice, Knockout; Multiprotein Complexes; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Protein Serine-Threonine Kinases; Protein Subunits; Reperfusion Injury; Tumor Necrosis Factor-alpha