期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 186, 期 10, 页码 2623-2636出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.06.009
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资金
- National Institute on Alcohol Abuse and Alcoholism [R01 AA020518, R01 DK102142]
- National Center for Research Resources [P20RR021940]
- National Institute of General Medical Sciences [P20 GM103549]
- National Institutes of Environmental Health Sciences [T32 ES007079]
- National Institute of General Medical Sciences of the NIH Institutional Development Award (IDeA) [P20 GM103418]
- University of Kansas Medical Center (KUMC) Research Institute
- NIH Clinical and Translational Science Award [UL1TR000001]
- NIH COBRE grant [9P20GM104936]
- NIH [S10RR027564]
How different cell death modes and cell survival pathways cross talk remains elusive. We determined the interrelation of apoptosis, necrosis, and autophagy in tumor necrosis factor (TNF)-alpha a/actinomycin D (ActD) and lipopolysaccharide/D-galactosamine (GalN)-induced hepatotoxicity in vitro and in vivo. We found that TNF-alpha/ActD-induced apoptosis was completely blocked by a general caspase inhibitor ZVAD-fmk at 24 hours but hepatocytes still died by necrosis at 48 hours. Inhibition of caspases also protected mice against lipopolysaccharide/GalN-induced apoptosis and liver injury at the early time point, but this protection was diminished after prolonged treatment by switching apoptosis to necrosis. Inhibition of receptor-interacting protein kinase (RIP)1 by necrostatin 1 partially inhibited TNF-alpha/ZVAD-induced necrosis in primary hepatocytes. Pharmacologic inhibition of autophagy or genetic deletion of Atg5 in hepatocytes did not protect against TNF-alpha/ActD/ZVAD-induced necrosis. Moreover, pharmacologic inhibition of RIP1 or genetic deletion of RIP3 failed to protect and even exacerbated liver injury after mice were treated with lipopolysaccharide/GalN and a pan-caspase inhibitor. In conclusion, our results suggest that different cell death mode and cell survival pathways are closely integrated during TNF-alpha-induced liver injury when both caspases and NF-kappa B are blocked. Moreover, results from our study also raised concerns about the safety of currently ongoing clinical trials that use caspase inhibitors.
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