Abstract
Abstract Sphingosine kinases are emerging a key enzymes in the intracellular signaling cascades, that mediate inflammatory responses, triggered by various inflammatory stimuli including: anaphylatoxins (C5a); bacterial-derived peptides (fMLP); and IgG or IgE receptor stimulation (FcγRI and FcεRI), in various immune cells, including in human mast cells. Moreover, we have recently reported a study on genome-wide gene expression profile of human mast cells sensitized with IgE alone, or stimulated by FcεRI aggregation, and found that sphingosine kinase 1 (SphK1) is one of the early genes to be activated. This, coupled to our previous studies indicating that SphK1 is pivotal in the signaling pathways initiated by FcεRI in human mast cells, prompted us to investigate the functional role of SphK1 in IgE-triggered inflammation/anaphylaxis in vivo. The systemic anaphylaxis reaction in mice has been considered to be a typical immediate hypersensitivity response determined by the activation of immune cells via antigen-induced aggregation of an IgE-sensitized FcεRI. To this end, we silenced the SPHK1 gene in vivo (using a specific siRNA), and investigated whether SphK1 knockdown influenced the outcome of the acute inflammatory responses, triggered during IgE-mediated systemic anaphylaxis in mice. We show here that, the siRNA for SphK1 protected mice from the IgE-mediated allergic reactions, including inhibition on: temperature changes; vascular permeability; immune-cell infiltration into organs; cytokine production; and vascular cell adhesion molecule expression. Thus, our findings strongly support a role for SpkK1 IgE-mediated anaphylaxis in vivo.