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.
Subject(s)
Concanavalin A/toxicity , Glutathione Peroxidase/metabolism , Lymphocyte Activation/drug effects , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Down-Regulation/drug effects , Enzyme Inhibitors/pharmacology , Glutathione Peroxidase/antagonists & inhibitors , Glutathione Peroxidase/genetics , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-2/genetics , Interleukin-2/metabolism , Jurkat Cells , Liver/injuries , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Stress/drug effects , Phosphorylation/drug effects , Reactive Oxygen Species/metabolism , Spleen/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Glutathione Peroxidase GPX1ABSTRACT
The inhibitory effects of four acidamides, piperine, pipernonaline, piperoctadecalidine, and piperlongumine, isolated from the fruits of Piper longum L. on washed rabbit platelet aggregation were examined. All of the four tested acidamides showed dose-dependent inhibitory activities on washed rabbit platelet aggregation induced by collagen, arachidonic acid (AA), and platelet-activating factor (PAF), except for that induced by thrombin. Piperlongumine, in particular, showed stronger inhibitory effects than other acidamides to rabbit platelet aggregation induced by collagen, AA and PAF.
