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 (DCs) 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 bone marrow-derived DCs under long-term inflammatory stimulation. We observed that differentiated cells undergo activation-induced cell death (AICD) upon LPS stimulation with an increased metabolic activity shortly after stimulation, followed by a rapid activation of caspase 3 and subsequent augmented apoptosis. Importantly, we highlight a profound role of Sphk1 in secretion of inflammatory cytokines and survival of dendritic cells that might be mediated by a change in sphingolipid levels as well as by a change in STAT3 expression. Cell growth during differentiation of Sphk1-deficient cells treated with the functional S1P receptor antagonist FTYP was reduced. Importantly, in dendritic cells we did not observe a compensatory regulation of Sphk2 mRNA in Sphk1-deficient cells. Instead, we discovered a massive increase in Sphk1 mRNA concentration 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 sphingolipids and Sphk1 in AICD during long-term immunogenic activity of DCs that might play an important role in autoimmunity and might explain the differences in immune response observed in in vivo studies of Sphk1 modulation.
Highlights
Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator and has been implicated in numerous physiological processes and diseases that affect several organs in humans (Maceyka et al, 2011)
S1P has been described in detail for its transactivating properties in cell proliferation induced by PDGF (Olivera and Spiegel, 1993), for the maintenance of islet viability (Lee et al, 2013), for its inhibition of histone deacetylases HDAC1/2 (Hait et al, 2009) and for its intracellular effects on the TRAF2/RIP1/NF-κB signaling pathway (Alvarez et al, 2010)
Immature Dendritic cells (DCs) of the spleen are replaced within 3–4 days (Kamath et al, 2000) suggesting a short DC lifespan regulated by programmed apoptotic cell death
Summary
Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator and has been implicated in numerous physiological processes and diseases that affect several organs in humans (Maceyka et al, 2011). Because of its diverse and potent bioactivity, the concentrations of S1P are tightly regulated by S1P-generating enzymes (Sphk1/2) and several S1P metabolizing enzymes, namely S1P phosphatases 1 and 2, lipid phosphate phosphatases 1–3 (Le Stunff et al, 2002) (Brindley and Pilquil, 2009) and S1P lyase which catalyzes an irreversible cleavage of S1P (Bandhuvula and Saba, 2007; Saba and de la Garza-Rodea, 2012). FTY720 (Fingolimod; Gilenya R ) is an immunemodulatory prodrug which, after intracellular phosphorylation (FTYP) by sphingosine kinase 2 and subsequent export, mimics effects of the endogenous lipid mediator S1P via S1P1, S1P3-5 receptors. Fingolimod has direct influences on immune cell function (Ottenlinger et al, 2016) and is able to accumulate intracellularly (Schroder et al, 2015)
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