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TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

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BADMANN, Anastasia, Stefanie LANGSCH, Adrian KEOGH, Thomas BRUNNER, Thomas KAUFMANN, Nadia CORAZZA, 2012. TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner. In: Cell Death and Disease. 3(12), e447. eISSN 2041-4889. Available under: doi: 10.1038/cddis.2012.185

@article{Badmann2012TRAIL-21458, title={TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner}, year={2012}, doi={10.1038/cddis.2012.185}, number={12}, volume={3}, journal={Cell Death and Disease}, author={Badmann, Anastasia and Langsch, Stefanie and Keogh, Adrian and Brunner, Thomas and Kaufmann, Thomas and Corazza, Nadia}, note={Article Number: e447} }

TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner Corazza, Nadia 2013-02-06T08:32:49Z Corazza, Nadia Brunner, Thomas Cell death & disease ; 3 (2012). - e447 Keogh, Adrian Badmann, Anastasia 2013-02-06T08:32:49Z Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. Kaufmann, Thomas deposit-license Kaufmann, Thomas Brunner, Thomas eng Keogh, Adrian Badmann, Anastasia 2012 Langsch, Stefanie Langsch, Stefanie

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