An emerging role for the lipid mediator sphingosine-1-phosphate in mast cell effector function and allergic disease.

Sphingosine-1-phosphate (S1P) plays important roles regulating functions of diverse biological systems, including the immune system. S1P affects immune cell function mostly by acting through its receptors at the cell membrane but it can also induce S1P receptor-independent responses in the cells where it is generated. S1P produced in allergically-stimulated mast cells mediates degranulation, cytokine and lipid mediator production and migration of mast cells towards antigen by mechanisms that are both S1P receptor-dependent and independent. Even in the absence of an antigen challenge, the differentiation and responsiveness of mast cells can be affected by chronic exposure to elevated S1P from a nonmast cell source, whichmay occur under pathophysiological conditions, potentially leading to the hyper-responsiveness of mast cells. The role of S1P extends beyond the regulation of the function of mast cells to the regulation of the surrounding or distal environment. S1P is exported out of antigen-stimulated mast cells and into the extracellular space and the resulting S1P gradient within the tissue may influence diverse surrounding tissue cells and several aspects of the allergic disease, such as inflammation or tissue remodeling. Furthermore, recent findings indicate that vasoactive mediators released systemically by mast cells induce the production of S1P in nonhematopoietic compartments, where it plays a role in regulating the vascular tone and reducing the hypotension characteristic of the anaphy lactic shock and thus helping the recovery. The dual actions of S1P, promoting the immediate response of mast cells, while controlling the systemic consequences of mast cell activity will be discussed in detail.