Tumor necrosis factor-alpha-mediated signal transduction in human neutrophils: involvement of sphingomyelin metabolites in the priming effect of TNF-alpha on the fMLP-stimulated superoxide production |
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Authors: | Niwa M Kozawa O Matsuno H Kanamori Y Hara A Uematsu T |
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Affiliation: | Department of Pharmacology, Gifu University School of Medicine, Japan. mniwa@cc.gifu-u.ac.jp |
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Abstract: | We investigated the mechanism underlying the priming effect of TNF-alpha on fMLP-stimulated superoxide production in human neutrophils. TNF-alpha enhanced fMLP-stimulated superoxide production in a concentration-dependent manner. TNF-alpha also induced sphingomyelin (SM) hydrolysis and increased the formation of its metabolite, sphingosine-1-phosphate (SP-1-P). The treatment of neutrophils with sphingomyelinase also resulted in a similar priming effect. C2 ceramide produced a concentration-dependent inhibition of fMLP-stimulated superoxide production within the concentration range of 1-30 microM. Sphingosine had a dual effect on fMLP-stimulated superoxide generation, exhibiting a priming effect at lower concentrations (0.2-1 microM), but an inhibitory effect at higher concentrations (1-30 microM). SP-1-P (1-30 microM), showed a concentration-dependent enhancement of fMLP stimulated superoxide production. Furthermore, after treating neutrophils with DL-threo-dihydro-sphingosine, a competitive inhibitor of sphingosine kinase, TNF-alpha produced a similar dual effect as observed with sphingosine. These results strongly suggest that SM hydrolysis plays a key role in the intracellular signal transduction mediating the TNF-alpha-mediated priming effect. |
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