TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner
| Autor: | Anastasia Badmann, Thomas Brunner, Stephanie Langsch, Nadia Corazza, Thomas Kaufmann, Adrian Keogh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Liver cytology paracetamol Apoptosis TRAIL TNF-Related Apoptosis-Inducing Ligand Liver disease Mice 0302 clinical medicine liver sinusoidal endothelial cells (LSEC) Caspase Cells Cultured Mice Knockout 0303 health sciences Bcl-2 homologs biology Bcl-2-Like Protein 11 Cell Death digestive oral and skin physiology 3. Good health Cell biology Endothelial stem cell medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Female Original Article Chemical and Drug Induced Liver Injury medicine.drug BH3 Interacting Domain Death Agonist Protein Programmed cell death Endothelium Immunology 610 Medicine & health 03 medical and health sciences Cellular and Molecular Neuroscience ddc:570 Cell Line Tumor Proto-Oncogene Proteins health services administration medicine Animals Humans 030304 developmental biology Acetaminophen organic chemicals Endothelial Cells Membrane Proteins Cell Biology medicine.disease Mice Inbred C57BL biology.protein Cancer research 570 Life sciences Apoptosis Regulatory Proteins |
| Zdroj: | Badmann, Anastasia; Langsch, Stephanie; Keogh, Adrian; Brunner, Thomas; Kaufmann, Thomas; Corazza, Nadia (2012). TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim-and Bid-dependent manner. Cell death & disease, 3(12), e447. London: Nature Publishing Group 10.1038/cddis.2012.185 Cell death & disease Cell Death & Disease |
| DOI: | 10.1038/cddis.2012.185 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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