LIPID MEDIATOR NETWORKS IN CELL SIGNALING - UPDATE AND IMPACT OF CYTOKINES

Biomembranes serve barrier functions and serve as a store for precurso rs of rapidly generated, structurally diverse intracellular and extrac ellular lipid-derived mediators (LM). Cell activation is accompanied b y remodeling of membrane components that appear to be essential in sig nal transduction. Phospholipases (PLA(2), PLC, PLD, sphingomyelinase) are pivotal in the generation of these LM including eicosanoids, plate let activating factor (PAF), diacylglycerides, ceramide, and other new ly discovered bioactive autacoids. Cytokines exert a dramatic multilev el impact both in regulating enzymes in individual LM pathways and in generating LM central to their action. Here, we provide an overview an d update of recent progress in this area with emphases on the effect o f cytokines on LM networks. The generation of eicosanoids (prostagland ins, leukotrienes, and lipoxins), oxygenated lipids, and PAF remain th e focus of rational drug design targets given their established roles in cell-cell communication and as mediators in inflammation and pathop hysiologic events. Key enzymes in these pathways are cloned, sequenced , and their subcellular organization is investigated with surprising f indings implicating involvement of the nuclear membrane at the functio nal level. Several LM receptors are identified and cloned, and results from transgenic animals have emerged for several key enzymes. Novel b ioactive eicosanoids were discovered, including 15-epi-lipoxins, isopr ostanes, and isoleukotrienes, that offered new concepts to consider in formation of LM and the actions of nonsteroidal anti-inflammatory dru gs. Together, these findings indicate that LM play critical and essent ial roles in both signal transduction and cell-cell communication and will continue to be important pathways to be considered in novel thera peutic approaches.