ArticleThe Journal of biological chemistry2009
IRAK-1 contributes to lipopolysaccharide-induced reactive oxygen species generation in macrophages by inducing NOX-1 transcription and Rac1 activation and suppressing the expression of antioxidative enzymes.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed, 108 citations in OpenAlex.
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- Protective Effects of Rhamnetin in Carbapenem-ResistantInternational journal of molecular sciences · 2023Article
- NOX1 mediates metabolic heart disease in mice and is upregulated in monocytes of humans with diastolic dysfunction.Cardiovascular research · 2022Article
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- Raising the 'Good' Oxidants for Immune Protection.Frontiers in immunology · 2021Review
- From Flies to Men: ROS and the NADPH Oxidase in Phagocytes.Frontiers in cell and developmental biology · 2021Review
- Neutrophil Extracellular Traps in the Autoimmunity Context.Frontiers in medicine · 2021Review
- PGC-1Oxidative medicine and cellular longevity · 2020Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Inflammatory stimulants such as bacterial endotoxin (lipopolysaccharide (LPS)) are known to induce tissue damage and injury partly through the induction of reactive oxygen species (ROS). Although it is recognized that the induction of ROS in macrophages by LPS depends upon the expression and activation of NADPH oxidase, as well as the suppression of antioxidative enzymes involved in ROS clearance, the underlying molecular mechanisms are poorly defined. In this study, we examined the contribution of the interleukin-1 receptor-associated kinase 1 (IRAK-1) to LPS-induced generation of ROS. We observed that LPS induced significantly less ROS in IRAK-1(-/-) macrophages, indicating that IRAK-1 is critically involved in the induction of ROS. Mechanistically, we observed that IRAK-1 is required for LPS-induced expression of NOX-1, a key component of NADPH oxidase, via multiple transcription factors, including p65/RelA, C/EBPbeta, and C/EBPdelta. On the other hand, we demonstrated that IRAK-1 associated with and activated small GTPase Rac1, a known activator of NOX-1 oxidase enzymatic activity. IRAK-1 forms a close complex with Rac1 via a novel LWPPPP motif within the variable region of IRAK-1. On the other hand, we also observed that IRAK-1 is required for LPS-mediated suppression of peroxisome proliferator-activated receptor alpha and PGC-1alpha, nuclear factors essential for the expression of antioxidative enzymes such as GPX3 and catalase. Consequently, injection of LPS causes significantly less plasma lipid peroxidation in IRAK-1(-/-) mice compared with wild type mice. Taken together, our study reveals IRAK-1 as a novel component involved in the generation of ROS induced by LPS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.