The omnific mediator system composed of sphingosine 1-phosphate (S1P) and its five G-protein-coupled receptors, designated S1P(1)-S1P(5), affects diverse cellular functions in the nervous, endocrine, cardiovascular and immune systems. The many activities of the S1P-S1P(1) axis, which predominates in the cardiovascular and immune systems, have previously been classified according to their relationship with the distinct functional roles of each type of cell or according to their most frequently used signalling pathways. In the immune system, cell surface S1P(1) receptors transduce the rapid, transient effects of extracellular S1P on T- and B-lymphocyte trafficking in the lymphoid system, lymphocyte migration in non-immune tissues and cytokine generation. After immune stimulation of T- and B-lymphocytes, S1P(1) receptors translocate from the cell surface to endosomal and nuclear compartments. The present hypothesis is that nuclear S1P(1) receptors represent distinct signalling complexes that, through a series of transcriptional events, transduce the sustained effects of intracellular S1P on survival and proliferation of T-lymphocytes. It is postulated that similar types of sustained signalling from nuclear S1P receptors in other types of cells affect proliferation, survival and specific effector functional activities. Effective pharmacological approaches to intracellular, as well as cell surface, S1P-S1P receptor axes will thus require the bioaccessibility of agonists and antagonists to the nuclear domain of relevant target cells.
Conclusion: Most investigations of the effects of the S1P-S1P(1) axis in immunity have focused primarily on rapid, transient alterations in lymphocyte migration and trafficking, and on mast cell migration and secretion of chemical mediators. The discovery of functional S1P(1)-G protein signalling complexes in the nuclear membranes of activated lymphocytes, that are coupled to the transduction of prolonged inhibition of proliferative responses by intracellular S1P, adds a new dimension to the role of the S1P-S1P(1) axis in immunity. Recruitment of this novel, potentially immunosuppressive, function of S1P(1) may be beneficial in some autoimmune diseases and will require application of cell membrane-permeant S1P(1)-specific drugs.