title: Toll-Like Receptor 4 Reduces Oxidative Injury via Glutathione Activity in Sheep.
abstract: Toll-like receptor 4 (TLR4) is an important sensor of Gram-negative bacteria and can trigger activation of the innate immune system. Increased activation of TLR4 can lead to the induction of oxidative stress. Herein, the pathway whereby TLR4 affects antioxidant activity was studied. In TLR4-overexpressing sheep, TLR4 expression was found to be related to the integration copy number when monocytes were challenged with lipopolysaccharide (LPS). Consequently, production of malondialdehyde (MDA) was increased, which could increase the activation of prooxidative stress enzymes. Meanwhile, activation of an antioxidative enzyme, glutathione peroxidase (GSH-Px), was increased. Real-time PCR showed that expression of activating protein-1 (AP-1) and the antioxidative-related genes was increased. By contrast, the expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) were reduced. In transgenic sheep, glutathione (GSH) levels were dramatically reduced. Furthermore, transgenic sheep were intradermally injected with LPS in each ear. The amounts of inflammatory infiltrates were correlated with the number of TLR4 copies that were integrated in the genome. Additionally, the translation of γ-glutamylcysteine synthetase (γ-GCS) was increased. Our findings indicated that overexpression of TLR4 in sheep could ameliorate oxidative injury through GSH secretion that was induced by LPS stimulation. Furthermore, TLR4 promoted γ-GCS translation through the AP-1 pathway, which was essential for GSH synthesis.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shoulong
authors.initials: S
authors.lastname: Deng
authors.affiliation: Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China ; State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.affiliation: School of Biological Science and Medical Engineering, Beijing University of Aeronautics and Astronautics, Beijing 100191, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Tianjin Institute of Animal Sciences, Tianjin 300112, China.
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Oceanic Administration, Beijing 100860, China.
authors.forename: Baolu
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
authors.forename: Guoshi
authors.initials: G
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yixun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China ; State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Zhengxing
authors.initials: Z
authors.lastname: Lian
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D005786:Gene Expression Regulation; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D012756:Sheep; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D005979:Glutathione Peroxidase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione