Activation-induced cell death in GM-CSF differentiated dendritic cells is dependent on Sphingosine kinase 1

Abstract

Sphingosine 1-phosphate (S1P) is an immune modulatory lipid mediator and has been implicated in numerous pathophysiological processes. S1P is produced by sphingosine kinase 1 (Sphk1) and Sphk2. Dendritic cells are central for the direction of immune responses and crucially involved in autoimmunity and cancerogenesis. In this study we examined the function and survival of dendritic cells under long-term inflammatory stimulation. We observed that GM-CSF differentiated dendritic cells undergo activation-induced cell death upon LPS stimulation with an increased metabolic activity after short-term stimulation followed by a rapid activation of caspase 3 and subsequent augmented apoptosis. Importantly, we highlighted a profound role of Sphk1 in secretion of inflammatory cytokines and survival of dendritic cells that might be mediated by a change in sphingolipid level as well as by a change in STAT3 expression. Cell expansion in Sphk1-deficient cells treated with the functional S1P receptor antagonist FTYP was reduced. Importantly, in dendritic cells we failed to find a compensatory upregulation of Sphk2 mRNA in SphK1-deficient cells. Instead, we observed a massive increase in Sphk1 mRNA level upon long-term stimulation with LPS in wild type cells that might function as an attempt to rescue from inflammation caused cell death. Taken together, in this investigation we describe details of a crucial involvement of sphingosine, S1P and Sphk1 in activation-induced cell death during long-term immunogenic activity of dendritic cells.