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 V alpha 14iNKT cell activation, IFN-gamma signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to V alpha 14iNKT cells deficiency, induced an anti-inflammatory response in the liver of J alpha 18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-gamma 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 V alpha 14iNKT 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 V alpha 14iNKT cells to impact inflammatory and pathological responses.
