Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages.

Sphingosine kinase 1 (SK1) and its product sphingosine-1-phosphate (S1P) have been implicated in the regulation of many cellular processes including growth regulation, protection from apoptosis, stimulation of angiogenesis, and most recently as mediators of the TNF-alpha inflammatory response. In this study we set out to examine the role of SK1/S1P in the RAW macrophage response to the potent inflammatory stimulus lipopolysaccharide (LPS). We show that LPS increases cellular levels of SK1 message and protein. This increase is at the transcriptional level and is accompanied by increased SK activity and generation of S1P. S1P is able to cause increases in COX-2 and PGE2 levels in RAW cells. Knockdown of SK1 using siRNA is able to inhibit the TNF but not the LPS inflammatory response. Moreover, knockdown of SK1 enhances both TNF- and LPS-induced apoptosis. These data indicate that there is a dual and distinct role for SK1 and S1P in the TNF and the LPS inflammatory pathways.