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Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice
- Publication Year :
- 2010
- Publisher :
- American Society for Clinical Investigation, 2010.
-
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.
- Subjects :
- Male
Settore MED/09 - Medicina Interna
medicine.medical_treatment
receptor
cd95
receptors
tissue inhibitor of metalloproteinase-3
protein structure, tertiary
cells, cultured
extracellular signal-regulated map kinases
hepatocytes
jnk mitogen-activated protein kinases
animals
drug-induced liver injury
apoptosis
receptor, epidermal growth factor
receptors, tumor necrosis factor, type i
signal transduction
mice
phosphorylation
antigens, cd95
cytoprotection
mice, inbred c57bl
adam proteins
proto-oncogene proteins c-akt
nf-kappa b
liver failure, acute
antigens
Receptor
Cells, Cultured
Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie
acute
General Medicine
ErbB Receptors
Cytokine
epidermal growth factor
Ectodomain
Receptors, Tumor Necrosis Factor, Type I
Chemical and Drug Induced Liver Injury
Signal transduction
inbred c57bl
Programmed cell death
tumor necrosis factor
ADAM17 Protein
Biology
Amphiregulin
medicine
fas Receptor
protein structure
Fulminant hepatitis
cultured
liver failure
type i
Liver Failure, Acute
Protein Structure, Tertiary
Mice, Inbred C57BL
tertiary
Apoptosis
Cancer research
cells
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....cbb9d80ca4fb9867b4fade7c30a07758