The critical roles of bioactive sphingolipids in inflammation.

The bioactivity of sphingosine (Sph), ceramides, sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) has been known for decades. However, the molecular mechanisms by which these sphingolipids exert their biological actions are not completely understood. Initial studies showed that Sph inhibited protein kinase C and phosphatidate phosphohydrolase activities paving the way for further discoveries on the key role these sphingolipids play in signal transduction processes. Soon after the implication of Sph in cell signaling events, it was shown that ceramides were also able to regulate relevant cell functions, including cell death and survival, differentiation, autophagy, and inflammation. Subsequent studies showed that both Sph and ceramides could be phosphorylated in cells and that S1P and C1P counteracted many of the actions elicited by ceramides. Both phosphorylated sphingolipids are essential for regulation of many physiological and pathological cell processes. The present review has been undertaken to highlight and clarify the molecular mechanisms and signaling pathways that are regulated by Sph, ceramides, S1P and C1P in cells with special attention been paid to understand the role of these bioactive sphingolipids in inflammatory responses and inflammation-associated diseases.