Glutathione transferase Omega 1 is required for the lipopolysaccharide-stimulated induction of NADPH oxidase 1 and the production of reactive oxygen species in macrophages

• Published in: Free radical biology & medicine Vol. 73; pp. 318 - 327
• Main Authors: Menon, Deepthi, Coll, Rebecca, O׳Neill, Luke A.J., Board, Philip G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2014
• Subjects: Active Transport, Cell Nucleus; Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Cell Line; Cytoskeletal Proteins; Free Radicals; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - genetics; Glutathione transferase Omega 1; Heat-Shock Proteins - genetics; Inflammation - immunology; Inflammation - pathology; Interleukin-1beta - biosynthesis; Interleukin-6 - biosynthesis; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; LPS; Macrophages - metabolism; Mice; NADH, NADPH Oxidoreductases - biosynthesis; NADPH Oxidase 1; NF-E2-Related Factor 2; NF-kappa B p50 Subunit - metabolism; Oxidation-Reduction; Oxidative Stress; PPAR gamma - biosynthesis; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering; TLR4; Toll-Like Receptor 4 - metabolism; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Glutathione transferase Omega 1; Free radicals; GPx3; GST; GR; MyD88; LPS; GCL; NF-κB; PPAR; Nrf2; IκκB; ROS; NADPH oxidase 1; GSH; TLR4; NOX1
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.05.020

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. [Display omitted] •GSTO1-1 regulates LPS-stimulated reactive oxygen species generation via TLR4.•GSTO1-1 decreases global protein glutathionylation levels in J774.1A macrophages.•NF-κB nuclear translocation is blocked in GSTO1-1-deficient J774.1A cells.