title: Glutathione transferase omega 1 is required for the lipopolysaccharide-stimulated induction of NADPH oxidase 1 and the production of reactive oxygen species in macrophages.
abstract: Bacterial lipopolysaccharide (LPS) stimulation of macrophages and inflammation via the Toll-like receptor 4 (TLR4) signaling pathway through NF-κΒ generates reactive oxygen species (ROS) and proinflammatory cytokines such as IL-1β, IL-6, and TNFα. Because glutathione transferase Omega 1-1 (GSTO1-1) can catalyze redox reactions such as the deglutathionylation of proteins and has also been implicated in the release of IL-1β we investigated its role in the development of LPS-mediated inflammation. Our data show that shRNA knockdown of GSTO1-1 in macrophage-like J774.1A cells blocks the expression of NADPH oxidase 1 and the generation of ROS after LPS stimulation. Similar results were obtained with a GSTO1-1 inhibitor. To maintain high ROS levels during an inflammatory response, LPS stimulation causes the suppression of enzymes such as catalase and glutathione peroxidase that protect against oxidative stress. The knockdown of GSTO1-1 also attenuates this response. Our data indicate that GSTO1-1 needs to be catalytically active and mediates its effects on the LPS/TLR4 inflammatory pathway upstream of NF-κΒ. These data suggest that GSTO1-1 is a novel target for anti-inflammatory intervention.
authors.affiliation: Department of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Menon
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin 2, Ireland.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Coll
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin 2, Ireland.
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: Department of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia. Electronic address: Philip.Board@anu.edu.au.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Board
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002460:Cell Line; D003598:Cytoskeletal Proteins; D005609:Free Radicals; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis*; D000074624:NADPH Oxidase 1; D051267:NF-E2-Related Factor 2; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047495:PPAR gamma / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005609:Free Radicals; C117709:Gsto1 protein, mouse; D006360:Heat-Shock Proteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D052002:NF-kappa B p50 Subunit; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D005982:Glutathione Transferase
keywords: Free radicals; Glutathione transferase Omega 1; LPS; NADPH oxidase 1; TLR4