title: Reduced oxidative tissue damage during endotoxemia in IRAK-1 deficient mice.
abstract: The generation of reactive oxygen species (ROS) triggered by bacterial endotoxin lipopolysaccharide (LPS) plays a key role during the pathogenesis of sepsis. Given the key role that the interleukin-1 receptor associated kinase-1 (IRAK-1) plays in LPS-mediated Toll-like-receptor 4 (TLR4) pathway, we herein tested whether deletion of IRAK-1 gene in mice may render protection from LPS-induced oxidative tissue damage. In this report, we studied the levels of oxidative stress in vital organs including liver, kidney, and brain from wild type (WT) and IRAK-1 deficient mice injected with a lethal dose of LPS (25mg/kg), a TLR4-specific agonist. We demonstrated that LPS challenge induced marked elevation of lipid peroxidation and nitrite levels in the plasma and tissues of WT mice, as well as elevated pro-inflammatory mediators. In contrast, IRAK-1 deficient mice had significantly lower lipid peroxidation and nitrite levels, as well as lower levels of pro-inflammatory mediators. Mechanistically, LPS triggered higher levels of iNOS activity and elevated membrane translocation of p47(phox), a key component of NADPH oxidase in immune cell derived from WT mice compared to IRAK-1 deficient mice. Additionally, tissues harvested from WT mice injected with LPS exhibited reduced activities of anti-oxidant enzymes including glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD). In contrast, LPS challenge failed to reduce the activities of GPx and SOD in IRAK-1 deficient tissues. As a consequence, LPS caused significantly pronounced damage to liver and kidney tissues in WT mice as compared to IRAK-1 deficient mice.
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Singh
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D019446:Endotoxemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000276:immunology*; D015227:Lipid Peroxidation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017382:Reactive Oxygen Species; D053592:Interleukin-1 Receptor-Associated Kinases