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

Downs I, Liu J, Aw TY, Adegboyega PA, Ajuebor MN - PLoS ONE (2012)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.

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.

Show MeSH

Related in: MedlinePlus

A proposed model depicting the sequential molecular and cellular events of NAC therapy regulation of Vα14iNKT cells signaling in the liver during Fas mAb-induced FLF.An endogenous mediator inhibited by NAC (possibly ROS) mediates Fas mAb-dependent FLF by promoting intrahepatic Vα14iNKT cells signaling, upregulation of pSTAT-1 and pSTAT-1-regulated genes, caspase 3 and T-bet, induction of hepatocyte damage and fatal/lethal immunopathological events in the liver that ultimately leads to FLF.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368940&req=5

pone-0038051-g005: A proposed model depicting the sequential molecular and cellular events of NAC therapy regulation of Vα14iNKT cells signaling in the liver during Fas mAb-induced FLF.An endogenous mediator inhibited by NAC (possibly ROS) mediates Fas mAb-dependent FLF by promoting intrahepatic Vα14iNKT cells signaling, upregulation of pSTAT-1 and pSTAT-1-regulated genes, caspase 3 and T-bet, induction of hepatocyte damage and fatal/lethal immunopathological events in the liver that ultimately leads to FLF.

Mentions: In summary, the current study reveals new insights into how NAC therapy regulates IFN-γ signaling in Vα14iNKT cells to impact inflammatory and pathological responses in the liver (Figure 5) and possibly other tissue sites (such as heart, lung and kidney) where Fas activation is often observed.


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

Downs I, Liu J, Aw TY, Adegboyega PA, Ajuebor MN - PLoS ONE (2012)

A proposed model depicting the sequential molecular and cellular events of NAC therapy regulation of Vα14iNKT cells signaling in the liver during Fas mAb-induced FLF.An endogenous mediator inhibited by NAC (possibly ROS) mediates Fas mAb-dependent FLF by promoting intrahepatic Vα14iNKT cells signaling, upregulation of pSTAT-1 and pSTAT-1-regulated genes, caspase 3 and T-bet, induction of hepatocyte damage and fatal/lethal immunopathological events in the liver that ultimately leads to FLF.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368940&req=5

pone-0038051-g005: A proposed model depicting the sequential molecular and cellular events of NAC therapy regulation of Vα14iNKT cells signaling in the liver during Fas mAb-induced FLF.An endogenous mediator inhibited by NAC (possibly ROS) mediates Fas mAb-dependent FLF by promoting intrahepatic Vα14iNKT cells signaling, upregulation of pSTAT-1 and pSTAT-1-regulated genes, caspase 3 and T-bet, induction of hepatocyte damage and fatal/lethal immunopathological events in the liver that ultimately leads to FLF.
Mentions: In summary, the current study reveals new insights into how NAC therapy regulates IFN-γ signaling in Vα14iNKT cells to impact inflammatory and pathological responses in the liver (Figure 5) and possibly other tissue sites (such as heart, lung and kidney) where Fas activation is often observed.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, United States of America.

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.

Show MeSH
Related in: MedlinePlus