The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and g...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2012-06, Vol.7 (6), p.e38051
Main Authors: Downs, Isaac, Liu, Jianfeng, Aw, Tak Yee, Adegboyega, Patrick A, Ajuebor, Maureen N
Format: Article
Language:English
Subjects:
Acetylcysteine
Acetylcysteine - pharmacology
Acetylcysteine - therapeutic use
Analysis of Variance
Animals
Antibodies, Monoclonal - adverse effects
Antibodies, Monoclonal - immunology
Antigens
Apoptosis
Apoptosis - physiology
Biology
Blotting, Western
Cell activation
Cytokines
Experiments
Fas Ligand Protein - immunology
Flow Cytometry
Free Radical Scavengers - pharmacology
Free Radical Scavengers - therapeutic use
Glutathione
Glutathione - metabolism
Health sciences
Immune system
In Situ Nick-End Labeling
Infections
Inflammation
Inflammatory response
Interferon
Interferon-gamma - genetics
Interferon-gamma - metabolism
Ligands
Liver
Liver - metabolism
Liver diseases
Liver failure
Liver Failure, Acute - chemically induced
Liver Failure, Acute - drug therapy
Liver Failure, Acute - immunology
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred C57BL
Mice, Knockout
Monoclonal antibodies
Natural Killer T-Cells - metabolism
Nitrotyrosine
Pathogens
Permeability
Physiology
Reactive Oxygen Species - metabolism
Rodents
Signal Transduction - drug effects
Signal Transduction - physiology
Signaling
T cell receptors
γ-Interferon
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0038051