The ability of pro-inflammatory cytokines such as interleukin-1β (IL-1β) to induce the major inflammatory mediator prostaglandin (PG) E 2 depends on the activation of two rate-limiting enzymes, phospholipase A2 (PLA2) and cyclooxygenase 2 (COX-2). PLA2 acts to generate arachidonic acid, which serves as the precursor substrate for COX-2 in the metabolic pathway leading to PGE2 production. However, less is known about the mechanisms that coordinate the regulation of these two enzymes. We have provided prior evidence that sphingosine kinase 1 and its bioactive lipid product sphingosine-1-phosphate (S1P) mediate the effects of cytokines on COX-2 induction, whereas ceramide kinase and its distinct product, ceramide-1-phosphate (C1P), are required for the activation and translocation of cPLA2 (FASEB J 17:1411-1421. 2003; J Biol Chem 278:38206-38213, 2003; J Biol Chem 279:11320-11326, 2004). Herein, we show that these two pathways are independent but coordinated, resulting in synergistic induction of PGE2. Moreover, the combination of both S1P and C1P recapitulates the temporal and spatial activation of cPLA2 and COX-2 seen with IL-1β. Taken together, the results provide, for the first time, a mechanism that assures the coordinate expression and activation in time and space of COX-2 and cPLA2, assuring maximal production of PGE2.
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