title: Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation.
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.
authors.affiliation: Medical Research Center, College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Medical Research Center, College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: D J
authors.initials: DJ
authors.lastname: Son
authors.affiliation: Medical Research Center, College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: M H
authors.initials: MH
authors.lastname: Park
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, 1, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: D Y
authors.initials: DY
authors.lastname: Yoon
authors.affiliation: Medical Research Center, College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Han
authors.affiliation: Medical Research Center, College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk 361-951, Republic of Korea.
authors.forename: J T
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003208:Concanavalin A / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D004791:Enzyme Inhibitors; D007376:Interleukin-2; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma; D005979:Glutathione Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000094765:Glutathione Peroxidase GPX1