Potential conflict of interest: Nothing to report.
The balancing act of hepatocyte apoptosis†
Article first published online: 23 NOV 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 52, Issue 6, pages 2231–2233, December 2010
How to Cite
Shackel, N. A. (2010), The balancing act of hepatocyte apoptosis. Hepatology, 52: 2231–2233. doi: 10.1002/hep.24007
- Issue published online: 23 NOV 2010
- Article first published online: 23 NOV 2010
The cell death receptor Fas plays a role in the establishment of fulminant hepatitis, a major cause of drug-induced liver failure. Fas activation elicits extrinsic apoptotic and hepatoprotective signals; however, the mechanisms by which these signals are integrated during disease are unknown. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls the critical sheddase a disintegrin and metalloproteinase 17 (ADAM17) and may dictate stress signaling. Using mice and cells lacking TIMP3, ADAM17, and ADAM17-regulated cell surface molecules, we have found that ADAM17-mediated ectodomain shedding of TNF receptors and EGF family ligands controls activation of multiple signaling cascades in Fas-induced hepatitis. We demonstrated that TNF signaling promoted hepatotoxicity, while excessive TNF receptor 1 (TNFR1) shedding in Timp3−/− mice was protective. Compound Timp3−/−Tnf−/− and Timp3−/−Tnfr1−/− knockout conferred complete resistance to Fas-induced toxicity. Loss of Timp3 enhanced metalloproteinase-dependent EGFR signaling due to increased release of the EGFR ligands TGF-α, amphiregulin, and HB-EGF, while depletion of shed amphiregulin resensitized Timp3−/− hepatocytes to apoptosis. Finally, adenoviral delivery of Adam17 prevented acetaminophen-induced liver failure in a clinically relevant model of Fas-dependent fulminant hepatitis. These findings demonstrate that TIMP3 and ADAM17 cooperatively dictate cytokine signaling during death receptor activation and indicate that regulated metalloproteinase activity integrates survival and death signals during acute hepatotoxic stress.