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

Author:
Singh, Neeraj, Li, Liwu
Source:
Molecular immunology 2012 v.50 no.4 pp. 244-252
ISSN:
0161-5890
Subject:
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
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 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.
Agid:
1138359