Mast cell activation is a central event in allergic diseases, and investigating the signalling pathways triggered during mast cell activation may lead to the discovery of novel therapeutic targets. Mast cells can be activated by a multitude of stimuli including antibodies/ antigen, cytokines/chemokines and neuropeptides, resulting in a variety of responses including the immediate release of potent inflammatory mediators. Moreover, recent data suggest that mast cell-mediated responses are also influenced by the differential sphingolipids/sphingosine to sphingosine-1-phosphate ratio. The importance of sphingolipids as potent biological mediators of both intracellular and extracellular responses is being increasingly recognized and accepted; it is now appreciated that activation of mast cells, via the high-affinity IgE-receptor (FceRI) leads to the activation of sphingosine kinases (SphK), resulting in increased formation of sphingosine-1-phosphate. Furthermore, FceRI activates SphK-dependent calcium mobilization in mast cells, leading to degranulation, cytokine, and eicosanoid production, and chemotaxis. In the past two years a critical role for SphK in allergic responses in vivo has emerged. In this review, I focus on the current understanding of the role of sphingosine kinases during mast cell signalling in vitro and their role during hypersensitivity responses in vivo, and discuss the potential of these enzymes as novel therapeutic targets to treat allergic diseases.Key words: Allergies . Mast cells . Sphingolipids . Sphingosine kinases . Therapeutic target
IntroductionThe triggering event in the initiation of an acute allergic attack is the interaction of normally innocuous substances, i.e. allergens, with IgE antibodies bound to the surface of mast cells, via the high-affinity IgE-receptor, FceRI. This initiates a number of biochemical pathways that ultimately result in mast cell degranulation, and the release of a variety of both pre-formed, and newly synthesized, inflammatory mediators [1]; however, mast cells are also known to play a role in delayed and/or chronic allergic responses such as asthma [1]. Figure 1 shows the principal pathways leading to acute and chronic allergic reactions. Mast cell activation triggered by FceRI leads to the activation of sphingosine kinase (SphK), which in turn changes the balance between sphingosine and sphingosine-1-phosphate (S1P), in favour of S1P [2][3][4][5]. These two lipids have opposite effects on immune cells [6]. In immune cells, sphingolipid metabolism is tightly related to stages of immune cell development, differentiation, activation, and proliferation -and manifested in the form of physiological responses such as survival, proliferation, calcium mobilization, cytoskeletal reorganization, chemotaxis, and eicosanoid and cytokine production [6][7][8][9]. Mini-Review processes [6]. S1P belongs to a new class of potent bioactive molecules, which are involved in a variety of cellular processes, including cell differentiation, proliferation, and migration [9][10][11...