Sphingolipids and the Balancing of Immune Cell Function: Lessons from the Mast Cell

Abstract

Recent studies reveal that metabolites of sphingomyelin are critically important for initiation and maintenance of diverse aspects of immune cell activation and function. The conversion of sphingomyelin to ceramide, sphingosine, or sphingosine-1-phosphate (S1P) provides interconvertible metabolites with distinct biological activities. Whereas ceramide and sphingosine function to induce apoptosis and to dampen mast cell responsiveness, S1P functions as a chemoattractant and can up-regulate some effector responses. Many of the S1P effects are mediated through S1P receptor family members (S1P1–5). S1P1, which is required for thymocyte emigration and lymphocyte recirculation, is also essential for Ag-induced mast cell chemotaxis, whereas S1P2 is important for mast cell degranulation. S1P is released to the extracellular milieu by Ag-stimulated mast cells, enhancing inflammatory cell functions. Modulation of S1P receptor expression profiles, and of enzymes involved in sphingolipid metabolism, particularly sphingosine kinases, are key in balancing mast cell and immune cell responses. Current efforts are unraveling the complex underlying mechanisms regulating the sphingolipid pathway. Pharmacological intervention of these key processes may hold promise for controlling unwanted immune responses.

Suppression of immunoglobulin E–mediated allergic responses by regulator of G protein signaling 13

“…Polymerase chain reaction (PCR) and microarray analysis of various sources of MC RNA for R4 RGS family members revealed expression of Rgs1, 8,13,16 13 and 18 (data not shown). We focused on Rgs13 because microarray studies of purified human cell subsets showed restricted RGS13 expression in MCs compared to other hematopoietic cells (Fig.…”

“…RGS isoforms can be further divided into subfamilies on the basis of additional protein interaction motifs. However, the R4 subfamily of 8,13,16,18,and 21) …”

“…RGS isoforms can be further divided into subfamilies on the basis of additional protein interaction motifs. However, the R4 subfamily of RGSs (RGS1-5, 8,13,16,18, and 21) contains only short peptide sequences flanking the RGS domain. Despite extensive characterization of their biochemical actions in vitro, the physiological function of most R4 RGS proteins remains unknown.…”

Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity

“…Maintenance of immunosuppression by FTY720, however, is associated with such a broad spectrum of serious ocular, pulmonary and cardiac complications that alternative agents and approaches are being sought which have S1P 1 R selectivity, a greater ratio of antagonist and downregulator functions to agonist activity, and preferential organ system effects. One very hopeful therapeutic possibility is a recently discovered cluster of monoclonal anti-S1P 1 Abs that inhibit lymphocyte functional responses to S1P. Two clear advantages of these monoclonal antibodies are absolute specificity and the greater ability to focus effective inhibitory concentrations of a protein than a small organic compound at a tissue site of involvement of the S1P-S1P 1 axis.…”

“…Sphingosine 1-phosphate (S1P), that is produced principally by stimulated mast cells and mononuclear phagocytes in tissues and by erythrocytes in blood [1,2], is a major mediator of T cell lymphoid traffic, tissue migration, proliferation and cytokine secretion [3][4][5][6]. Of the family of G protein-coupled receptors (GPCRs) with high specificity for S1P, the type 1 receptor (S1P 1 ) predominates in its level of expression and transduction of diverse T cell functional responses [7,8].…”