Abstract
The mechanism underlying the protective effect of sphingosine kinase 1 (SphK1) in inflammatory injury is not clear. We demonstrated using SphK1-null mice (SphK1(-/-)) the crucial role of SphK1 in suppressing lipopolysaccharide-induced neutrophil oxidant production and sequestration in lungs and mitigating lung inflammatory injury. This effect of SphK1 was independent of the production of sphingosine 1-phosphate, the product of SphK1 activity. The anti-inflammatory effect of SphK1 in the lipopolysaccharide model was mediated through SphK1 interaction with JNK. SphK1 stabilization of JNK in turn inhibited JNK binding to the JNK-interacting protein 3 (JIP3) and thus abrogated the activation of NADPH oxidase and oxidant generation and resultant NF-kappaB activation. Therefore, SphK1-mediated down-regulation of JNK activity serves to dampen inflammation and tissue injury.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Down-Regulation / genetics
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Down-Regulation / radiation effects
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Lipopolysaccharides / toxicity*
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Lung / enzymology*
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Lysophospholipids / genetics
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Lysophospholipids / metabolism
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism*
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Mice
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Mice, Knockout
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neutrophils / enzymology*
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Oxidants / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Pneumonia / chemically induced
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Pneumonia / enzymology*
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Pneumonia / genetics
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Sphingosine / analogs & derivatives
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Sphingosine / genetics
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Sphingosine / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Lipopolysaccharides
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Lysophospholipids
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MAPK8IP3 protein, human
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Nerve Tissue Proteins
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Oxidants
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sphingosine 1-phosphate
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NADPH Oxidases
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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MAP Kinase Kinase 4
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Sphingosine