Abstract
We and others have previously shown that the inducible nitric-oxide synthase (iNOS) and nitric oxide (NO) are hepatoprotective in a number of circumstances, including endotoxemia. In vitro, hepatocytes are protected from tumor necrosis factor (TNF) α-induced apoptosis via cGMP-dependent and cGMP-independent mechanisms. We have shown that the cGMP-dependent protective mechanisms involve the inhibition of death-inducing signaling complex formation. We show here that LPS-induced iNOS expression leads to rapid TNF receptor shedding from the surface of hepatocytes via NO/cGMP/protein kinase G-dependent activation and surface translocation of TNFα-converting enzyme (TACE/ADAM17). The activation of TACE is associated with the up-regulation of iRhom2 as well as the interaction and phosphorylation of TACE and iRhom2, which are also NO/cGMP/protein kinase G-dependent. These findings suggest that one mechanism of iNOS/NO-mediated protection of hepatocytes involves the rapid shedding of TNF receptor 1 to limit TNFα signaling.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
ADAM Proteins / genetics
-
ADAM Proteins / metabolism*
-
ADAM17 Protein
-
Animals
-
Carrier Proteins / biosynthesis
-
Carrier Proteins / genetics
-
Cells, Cultured
-
Cyclic GMP / genetics
-
Cyclic GMP / metabolism*
-
Enzyme Activation / drug effects
-
Enzyme Activation / genetics
-
Hepatocytes / cytology
-
Hepatocytes / metabolism*
-
Lipopolysaccharides / pharmacology
-
Male
-
Mice
-
Mice, Knockout
-
Nitric Oxide / genetics
-
Nitric Oxide / metabolism
-
Nitric Oxide Synthase Type II / genetics
-
Nitric Oxide Synthase Type II / metabolism*
-
Phosphorylation / drug effects
-
Phosphorylation / physiology
-
Protein Transport / drug effects
-
Protein Transport / genetics
-
Receptors, Tumor Necrosis Factor, Type I / genetics
-
Receptors, Tumor Necrosis Factor, Type I / metabolism*
-
Signal Transduction / drug effects
-
Signal Transduction / physiology*
-
Tumor Necrosis Factor-alpha / genetics
-
Tumor Necrosis Factor-alpha / metabolism
-
Up-Regulation / drug effects
-
Up-Regulation / physiology
Substances
-
Carrier Proteins
-
Lipopolysaccharides
-
Receptors, Tumor Necrosis Factor, Type I
-
Tnfrsf1a protein, mouse
-
Tumor Necrosis Factor-alpha
-
iRhom2 protein, mouse
-
lipopolysaccharide, Escherichia coli O111 B4
-
Nitric Oxide
-
Nitric Oxide Synthase Type II
-
Nos2 protein, mouse
-
ADAM Proteins
-
ADAM17 Protein
-
Adam17 protein, mouse
-
Cyclic GMP