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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 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.

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.

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Effect of NAC treatment on intrahepatic Vα14iNKT cell accumulation during Fas mAb-induced FLF.(a) Representative FACS dot plot of Vα14iNKT cells levels in the liver after PBS or NAC treatment during Fas mAb-induced FLF. (b) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment in response to Fas mAb-induced FLF. (c) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment only (i.e. in the absence of agonistic Fas mAb). Results in b and c are shown as mean ± s.e.m with n = 4–6 mice/group with *P<0.05 by Student’s unpaired t test. All experiments were conducted twice. Broken lines denote levels in untreated mice.
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pone-0038051-g004: Effect of NAC treatment on intrahepatic Vα14iNKT cell accumulation during Fas mAb-induced FLF.(a) Representative FACS dot plot of Vα14iNKT cells levels in the liver after PBS or NAC treatment during Fas mAb-induced FLF. (b) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment in response to Fas mAb-induced FLF. (c) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment only (i.e. in the absence of agonistic Fas mAb). Results in b and c are shown as mean ± s.e.m with n = 4–6 mice/group with *P<0.05 by Student’s unpaired t test. All experiments were conducted twice. Broken lines denote levels in untreated mice.

Mentions: Given the anti-inflammatory effects of NAC therapy on Fas mAb-dependent FLF and Th1 differentiating signaling, we next determined whether NAC may also inhibit intrahepatic Vα14iNKT cell accumulation. Indeed, we found that NAC therapy effectively diminished the frequency of Vα14iNKT cells in the liver of WT mice undergoing acute FLF (Figure 4A and B). It is also notable that the frequency of Vα14iNKT cells in the liver of WT mice treated only with NAC (i.e. in the absence of agonistic Fas mAb) did not significantly differ from WT mice given only PBS (Figure 4C), suggesting that endogenous ROS produced in inflamed liver during agonistic Fas mAb-mediated FLF may be driving the effects seen on intrahepatic Vα14iNKT cell accumulation.


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)

Effect of NAC treatment on intrahepatic Vα14iNKT cell accumulation during Fas mAb-induced FLF.(a) Representative FACS dot plot of Vα14iNKT cells levels in the liver after PBS or NAC treatment during Fas mAb-induced FLF. (b) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment in response to Fas mAb-induced FLF. (c) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment only (i.e. in the absence of agonistic Fas mAb). Results in b and c are shown as mean ± s.e.m with n = 4–6 mice/group with *P<0.05 by Student’s unpaired t test. All experiments were conducted twice. Broken lines denote levels in untreated mice.
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Related In: Results  -  Collection

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pone-0038051-g004: Effect of NAC treatment on intrahepatic Vα14iNKT cell accumulation during Fas mAb-induced FLF.(a) Representative FACS dot plot of Vα14iNKT cells levels in the liver after PBS or NAC treatment during Fas mAb-induced FLF. (b) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment in response to Fas mAb-induced FLF. (c) FACS analysis of Vα14iNKT cells level in the liver after PBS or NAC treatment only (i.e. in the absence of agonistic Fas mAb). Results in b and c are shown as mean ± s.e.m with n = 4–6 mice/group with *P<0.05 by Student’s unpaired t test. All experiments were conducted twice. Broken lines denote levels in untreated mice.
Mentions: Given the anti-inflammatory effects of NAC therapy on Fas mAb-dependent FLF and Th1 differentiating signaling, we next determined whether NAC may also inhibit intrahepatic Vα14iNKT cell accumulation. Indeed, we found that NAC therapy effectively diminished the frequency of Vα14iNKT cells in the liver of WT mice undergoing acute FLF (Figure 4A and B). It is also notable that the frequency of Vα14iNKT cells in the liver of WT mice treated only with NAC (i.e. in the absence of agonistic Fas mAb) did not significantly differ from WT mice given only PBS (Figure 4C), suggesting that endogenous ROS produced in inflamed liver during agonistic Fas mAb-mediated FLF may be driving the effects seen on intrahepatic Vα14iNKT cell accumulation.

Bottom Line: 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.

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