Lipid mediator networks in cell signaling: update and impact of cytokines

Biomembranes serve barrier functions and serve as a store for precursors of rapidly generated, structurally diverse intracellular and extracellular lipid-derived mediators (LM). Cell activation is accompanied by remodeling of membrane components that appear to be essential in signal transduction. Phospholipases (PLA2, PLC, PLD, sphingomyelinase) are pivotal in the generation of these LM including eicosanoids, platelet activating factor (PAF), diacylglycerides, ceramide, and other newly discovered bioactive autacoids. Cytokines exert a dramatic multilevel impact both in regulating enzymes in individual LM pathways and in generating LM central to their action. Here, we provide an overview and update of recent progress in this area with emphasis on the effect of cytokines on LM networks. The generation of eicosanoids (prostaglandins, leukotrienes, and lipoxins), oxygenated lipids, and PAF remain the focus of rational drug design targets given their established roles in cell-cell communication and as mediators in inflammation and pathophysiologic events. Key enzymes in these pathways are cloned, sequenced, and their subcellular organization is investigated with surprising findings implicating involvement of the nuclear membrane at the functional level. Several LM receptors are identified and cloned, and results from transgenic animals have emerged for several key enzymes. Novel bioactive eicosanoids were discovered, including 15-epi-lipoxins, isoprostanes, and isoleukotrienes, that offered new concepts to consider in formation of LM and the actions of nonsteroidal anti-inflammatory drugs. Together, these findings indicate that LM play critical and essential roles in both signal transduction and cell-cell communication and will continue to be important pathways to be considered in novel therapeutic approaches.-Serhan, C. N., Haeggström, J. Z., Leslie, C. C. Lipid mediator networks in cell signaling: update and impact of cytokines.