Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation

Abstract

Sphingolipids and their synthetic enzymes are emerging as important mediators in inflammatory responses and as regulators of immune cell functions. In particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P) have been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. SK1 has been shown to be activated by cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin1-beta (IL1-beta). The activation of SK1 in this pathway has been shown to be, at least in part, required for mediating TNF-alpha and IL1-beta inflammatory responses in cells, including induction of cyclo-oxygenase 2 (COX2). In addition to their role in inflammatory signaling, SK and S1P have also been implicated in various immune cell functions including, mast cell degranulation, migration of neutrophils, and migration and maturation of lymphocytes. The involvement of sphingolipids and sphingolipid metabolizing enzymes in inflammatory signaling and immune cell functions has implicated these mediators in numerous inflammatory disease states as well. The contribution of these mediators, specifically SK1 and S1P, to inflammation and disease are discussed in this review.

Figure 1. Pathways of Sphingolipid Metabolism

Production of bioactive sphingolipids ceramide, sphingosine, and S1P occurs through de novo synthesis or the salvage pathway. De novo synthesis involves the condensation of serine and palmitoyl CoA by serine palmitoyl transferase for form 3-keto-sphinganine, which is rapidly reduced to dihydrosphingosine by an NADPH-dependent reductase. Dihydrosphingosine is converted to dihydroceramide with the addition of fatty acyl CoA by dihydroceramide synthase which is desaturated to form ceramide. Ceramide can be converted to glycosphingolipids by glucosylceramide synthase and back to ceramide by glucosylceramidase. Ceramide can also be formed by the salvage pathway through the action of sphinogmyelinases. Ceramide can be phosphorylated to ceramide-1-phosphate or deacylated by ceramidase to form sphingosine. Sphingosine is quickly phosphorylated by sphingosine kinase to form S1P. S1P can be dephosphorylated by S1P phosphatases, forming sphingosine, which can be converted back to ceramide with the addition of free fatty acid by ceramide synthases. S1P can be terminally degraded by S1P lyase to form hexadecanal and phosphoethanolamine. FFA: free fatty acid, Glu-Cer Synthase: glucosylceramide synthase, Glu-CDase: Glucosylceramidase.

Figure 2. Inside-out S1P Signaling

Various agonists or stimuli bind and activate their respective receptors, leading to the activation of the SK/S1P pathway by both known and unknown mechanisms. Shown are molecules implicated in the phosphorylation (ERK and PKC) and/or the activation (PLD) of SK. Once activated by phosphorylation or by undefined mechanisms, SK is thought to translocate to the plasma membrane where it comes into contact with its substrate, sphingosine. SK then catalyzes the formation of S1P, which can act as an intracellular signaling molecule, or it can be exported via ABCC transporters to act in an autocrine or paracrine manner. Once activated, S1PRs elicit specific G-protein-mediated signals and this is followed by receptor internalization. Receptors are then recycled or degraded. ERK: extracellular regulated kinase; PKC: protein kinase c; PLD: phospholipase D; SK: sphingosine kinase; S1P: sphingosine 1-phosphate; S1PRs: sphingosine 1-phosphate receptors.