Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation.

D H Lee,M H Park,D Y Yoon,D J Son,S B Han,J T Hong

doi:10.1038/cddis.2016.95

Abstract

Concanavalin A (Con A)-induced hepatitis model is well-established experimental T cell-mediated liver disease. Reactive oxygen species (ROS) is associated with T-cell activation and proliferation, but continued ROS exposure induces T-cell hyporesponsiveness. Because glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme and is involved in T-cell development, we investigated the role of Gpx1 during Con A-induced liver injury in Gpx1 knockout (KO) mice. Male wild-type (WT) mice and Gpx1 KO mice were intravenously injected with Con A (10 mg/kg), and then killed after 8 h after Con A injection. Serum levels of aspartate transaminase and alanine transaminase were measured to assess hepatic injury. To identify that Gpx1 affects T cell-mediated inflammation, we pretreated Gpx1 inhibitor to Human Jurkat T cells then treated Con A. Con A-induced massive liver damage in WT mice but its damage was attenuated in Gpx1 KO mice. Con A-induced Th1 cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-2 were also decreased in the liver and spleen of Gpx1 KO mice compared with WT mice. In Jurkat T cells, Con A-induced mRNA levels of IL-2, IFN-γ and TNF-α were downregulated by pretreatment of Gpx inhibitor, mercaptosuccinic acid. We also observed that Gpx1 KO mice showed increasing oxidative stress in the liver and spleen compared with WT mice. These results suggest that Gpx1 deficiency attenuates Con A-induced liver injury by induction of T-cell hyporesponsiveness through chronic ROS exposure.

Highlights

CD4+ T helper (Th) cells, but not cytotoxic CD8+ T cells, were major factor in Concanavalin A (Con A)-induced liver injury
Gpx activity in the liver of WT mice was increased by Con A injection, and it was decreased in the liver of both saline- and Con A-injected Gpx[1] KO mice (Figure 1b)
Con A-injected mice showed low GSH/GSSG ratio, increased hydrogen peroxide and high MDA level in the liver and spleen compared with Con A-injected WT mice (Figure 6). These results suggest that Gpx[1] deficiency attenuates Con A-induced T-cell activation through continued Reactive oxygen species (ROS)-induced T-cell hyporesponsiveness

Summary

Introduction

CD4+ T helper (Th) cells, but not cytotoxic CD8+ T cells, were major factor in Con A-induced liver injury. Reactive oxygen species (ROS) are highly reactive and likely to destroy biological structure, promoting cellular damage and progression inflammatory disease.[7] recently published studies showed opposing the traditional concept on ROS, which is the protective role of ROS in immune-mediated inflammatory disease.[8] Mice with low concentration of ROS due to defects of ROS-producing enzyme such as Ncf[1] are more susceptible to autoimmune disease.[9] Humans with lower levels of ROS such as patients with chronic granulomatous disease (CGD) than normal persons are more susceptible to autoimmune disease.[10,11] the pharmacological antioxidant N-acetylcystein (NAC) enhances T-cell function and proliferation by inhibition of nuclear factor-κB (NF-κB).[12,13] Cermerski et al.[14] reported that T lymphocytes that are isolated form peripheral blood rendered hyporesponsive by exposure to an oxidative environment through inactivation of phospholipase C-γ (PLCγ) These results suggest that ROS level is important in T-cell activation and proliferation. We developed a model of Con A-induced acute liver injury in Gpx1-deficient mice and investigated the role of Gpx[1] in T cell-mediated hepatic injury

Methods

Results

Conclusion