title: Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice.
abstract: 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-alpha, 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.
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Aditya
authors.initials: A
authors.lastname: Murthy
authors.forename: Virginie
authors.initials: V
authors.lastname: Defamie
authors.forename: David S
authors.initials: DS
authors.lastname: Smookler
authors.forename: Marco A
authors.initials: MA
authors.lastname: Di Grappa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D019610:Cytoprotection; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D017114:Liver Failure, Acute / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D015398:Signal Transduction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D019717:Tissue Inhibitor of Metalloproteinase-3; C506236:Tnfrsf1a protein, mouse; D019014:fas Receptor; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse