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.