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-kappa B

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-kappaB activation and reactive oxygen species (ROS) production. In this study, we present the data that LPS-induced ROS ge...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2004-09, Vol.173 (6), p.3589-3593
Main Authors: Park, Hye Sun, Jung, Hye Young, Park, Eun Young, Kim, Jaesang, Lee, Won Jae, Bae, Yun Soo
Format: Article
Language:English
Subjects:
Cell Line
Humans
Isoenzymes - deficiency
Isoenzymes - genetics
Isoenzymes - physiology
Lipopolysaccharides - antagonists & inhibitors
Lipopolysaccharides - pharmacology
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - physiology
NADPH Oxidase 4
NADPH Oxidases - deficiency
NADPH Oxidases - genetics
NADPH Oxidases - physiology
NF-kappa B - antagonists & inhibitors
NF-kappa B - genetics
NF-kappa B - metabolism
Reactive Oxygen Species - metabolism
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Cell Surface - physiology
RNA, Messenger - antagonists & inhibitors
RNA, Messenger - biosynthesis
Toll-Like Receptor 4
Toll-Like Receptors
Transfection
U937 Cells
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Summary: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-kappaB activation and reactive oxygen species (ROS) production. In this study, we present the data that LPS-induced ROS generation and NF-kappaB 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-kappaB activation. Taken together, these results indicate that direct interaction of TLR4 with Nox4 is involved in LPS-mediated ROS generation and NF-kappaB activation.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.173.6.3589