Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-κB
Open accessAbstract
LPS, the primary constituent of the outer membrane of Gram-negative bacteria, is recognized by TLR4. Binding of TLR4 to LPS triggers various cell signaling pathways including NF-κB activation and reactive oxygen species (ROS) production. In this study, we present the data that LPS-induced ROS generation and NF-κB activation are mediated by a direct interaction of TLR4 with (NAD(P)H oxidase 4 (Nox) 4), a protein related to gp91phox (Nox2) of phagocytic cells, in HEK293T cells. Yeast two hybrid and GST pull-down assays indicated that the COOH-terminal region of Nox4 interacted with the cytoplasmic tail of TLR4. Knockdown of Nox4 by transfection of small interference RNA specific to the Nox4 isozyme in HEK293T cells expressing TLR4 along with MD2 and CD14 resulted in inhibition of LPS-induced ROS generation and NF-κB activation. Taken together, these results indicate that direct interaction of TLR4 with Nox4 is involved in LPS-mediated ROS generation and NF-κB activation.
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In the NF-κB system, NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB; pro-inflammatory cytokines such as TNF-α, LPS and IL-1 act by binding to receptors at the cell surface and initiating signalling pathways that lead to activation of IKK; IKK phosphorylates IκB causing its release and degradation, allowing NF-κB to translocate to the nucleus where it can activate a
“In the NF-κB system (e.g. [2020-2024]) (Fig 8), NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB (often IκBα). Pro-inflammatory cytokines such as TNF-α, LPS [2025-2030] and IL-1 [2031] act by binding to receptors at the cell surface and initiating signalling pathways that lead to the activation of a particular kinase, IκB kinase or IKK. This kinase phosphorylates the”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2029]
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- Authors
- Park, H. S., Jung, H. Y., Park, E. Y., Kim, J., Lee, W. J., & Bae, Y. S.
- Affiliations
- Ewha Womans University (KR)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-09
- Volume
- 173
- Issue
- 6
- Pages
- 3589-3593
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1585390661
- Cited by
- 635
- References
- 28
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 13 · 2023: 26 · 2022: 31 · 2021: 39 · 2020: 30 · 2019: 27 · 2018: 35 · 2017: 29 · 2016: 33 · 2015: 26 · 2014: 24 · 2013: 33 · 2012: 33
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ewha Womans University
- Korea Science and Engineering Foundation
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- TLR4, NOX4, lipopolysaccharide, reactive oxygen species, NF-κB activation, MD-2, CD14, HEK293T cells, siRNA knockdown
- MeSH terms
- NADPH Oxidase 4, Cell Line, Humans, Isoenzymes, Lipopolysaccharides, Membrane Glycoproteins, Receptors, Cell Surface, RNA, Messenger, Transfection, NF-kappa B, Reactive Oxygen Species, NADPH Oxidases, U937 Cells, Toll-Like Receptors, Toll-Like Receptor 4
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