Sphingolipids in inflammation: pathological implications and potential therapeutic targets

Abstract

Sphingolipids are formed via the metabolism of sphingomyelin, a constituent of the plasma membrane, or by de novo synthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in inflammation. This can involve, for example, activation of pro-inflammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-inflammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-affinity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on inflammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in inflammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and inflammatory bowel disease, which involve important inflammatory components. A significant body of research now indicates that sphingolipids are intimately involved in the inflammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological inflammation.

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

“…It is known that sphingolipids play essential roles in the induction and progress of inflammation (28), but only few publications deal with the role of specific ceramides in the inflammatory process (29). For the first time, to our knowledge, we show that CerS6 and its product, C 16:0 -Cer, specifically contribute to the inflammatory process by inducing iNOS and TNF-a expression in the initial phase of EAE.…”

HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate

“…A rapidly expanding literature further suggests that HDL-associated S1P is responsible, at least in part, for many of the benefi cial effects of HDL on vasorelaxation, cell survival, cell adhesiveness, angiogenesis, and the synthesis of two powerful antiatherogenic and antithrombotic molecules, nitric oxide and prostacyclin ( 30 ). There is emerging literature, however, to suggest that S1P may also mediate proatherogenic metabolism ( 20 ) in part because of its integral involvement in infl ammation ( 31 ) and may even function as a biomarker of obstructive coronary artery disease ( 32 ). We now demonstrate that S1P, especially the HDL3 subfraction which contains higher amounts of S1P than the HDL2 subfraction, signifi cantly increases PAI-1 secretion from adipocytes and, thus, may negatively modulate fi brinolysis in vivo.…”

Activation of Ceramidase and Ceramide Kinase by Vanadate via a Tyrosine Kinase–Mediated Pathway

“…It is becoming apparent that ceramide metabolites can be involved in inflammation (4,5). For example, ceramide and its metabolites regulate activation of cytosolic phospholipase A 2 α, release of arachidonic acid, and induction of cyclooxygenase-2, etc.…”