Sphingosine kinase signalling in immune cells: potential as novel therapeutic targets.

摘要: During the last few years, it has become clear that sphingolipids are sources of important signalling molecules. Particularly, sphingolipid metabolites, ceramide and S1P, have emerged as a new class potent bioactive molecules, implicated in variety cellular processes such cell differentiation, apoptosis, proliferation. Sphingomyelin (SM) is major membrane precursor for products. Ceramide formed from SM by action sphingomyelinases (SMase), however, can be very rapidly hydrolysed, ceramidases to yield sphingosine, sphingosine phosphorylated kinase (SphK) S1P. In immune cells, metabolism tightly related main stages development, activation, proliferation, transduced into physiological responses survival, calcium mobilization, cytoskeletal reorganization chemotaxis. Several biological effectors been shown promote synthesis including growth factors, cytokines, antigen G-protein-coupled receptor agonists. Interest S1P focused recently on two distinct actions this lipid, namely its function an intracellular second messenger, capable triggering release internal stores, extracellular ligand activating specific G protein-coupled receptors. Inhibition SphK stimulation strongly reduced or even prevented events triggered several proinflammatory agonists, receptor-stimulated DNA synthesis, Ca(2+) degranulation, chemotaxis cytokine production. Another observation direct role played chemotaxis, escape apoptosis. As mediator, studies now binds number receptors (GPCR) encoded endothelial differentiation genes (EDG), collectively known S1P-receptors. Binding these trigger wide range enhanced matrix assembly, adherent junctions, formation actin stress fibres, inhibition apoptosis induced either factor withdrawal. Moreover, blocking S1P1-receptor inhibits lymphocyte egress lymphatic organs. This review summarises evidence linking pathway immune-cell activation based data discuss potential targeting SphKs suppress inflammation other pathological conditions.