A novel function of sphingosine kinase 1 suppression of JNK activity in preventing inflammation and injury.

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.

• Authors: Anke Di, Takeshi Kawamura, Xiao-Pei Gao, Haiyang Tang, Evgeny Berdyshev, Stephen M Vogel, You-Yang Zhao, Tiffany Sharma, Kurt Bachmaier, Jingsong Xu, Asrar B Malik
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 21 Pg. 15848-57 (May 21 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20299461 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Lipopolysaccharides
• Lysophospholipids
• MAPK8IP3 protein, human
• Nerve Tissue Proteins
• Oxidants
• sphingosine 1-phosphate
• NADPH Oxidases
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• MAP Kinase Kinase 4
• Sphingosine

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Down-Regulation (genetics, radiation effects)
• Enzyme Activation (drug effects, genetics)
• Lipopolysaccharides (toxicity)
• Lung (enzymology)
• Lysophospholipids (genetics, metabolism)
• MAP Kinase Kinase 4 (genetics, metabolism)
• Mice
• Mice, Knockout
• NADPH Oxidases (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Neutrophils (enzymology)
• Oxidants (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (genetics, metabolism)
• Pneumonia (chemically induced, enzymology, genetics)
• Sphingosine (analogs & derivatives, genetics, metabolism)