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

PLoS One. 2012;7(6):e38051. doi: 10.1371/journal.pone.0038051. Epub 2012 Jun 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcysteine / pharmacology*
  • Acetylcysteine / therapeutic use
  • Analysis of Variance
  • Animals
  • Antibodies, Monoclonal / adverse effects*
  • Antibodies, Monoclonal / immunology
  • Apoptosis / physiology
  • Blotting, Western
  • Fas Ligand Protein / immunology
  • Flow Cytometry
  • Free Radical Scavengers / pharmacology*
  • Free Radical Scavengers / therapeutic use
  • Glutathione / metabolism
  • In Situ Nick-End Labeling
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Liver / metabolism
  • Liver Failure, Acute / chemically induced*
  • Liver Failure, Acute / drug therapy*
  • Liver Failure, Acute / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology

Substances

  • Antibodies, Monoclonal
  • Fas Ligand Protein
  • Free Radical Scavengers
  • Reactive Oxygen Species
  • Interferon-gamma
  • Glutathione
  • Acetylcysteine