Abstract

The ability of pro-inflammatory cytokines such as interleukin-1β (IL-1β) to induce the major inflammatory mediator prostaglandin (PG) E₂ 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 with COX-2 seen 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.