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Reduced oxidative tissue damage during endotoxemia in IRAK-1 deficient mice

Singh, Neeraj, Li, Liwu
Molecular immunology 2012 v.50 no.4 pp. 244-252
NAD(P)H oxidase (H2O2-forming), NADP (coenzyme), Toll-like receptor 4, agonists, antioxidant activity, brain, catalase, endotoxemia, endotoxins, genes, glutathione peroxidase, inducible nitric oxide synthase, interleukin-1, kidneys, lethal dose, lipid peroxidation, lipopolysaccharides, liver, mice, nitrites, oxidative stress, pathogenesis, reactive oxygen species, sepsis (infection), superoxide dismutase
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 p47ᵖʰᵒˣ, 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.