Bacterial lipopolysaccharides modify signal transduction in the arachidonic acid cascade in macrophages

Macrophages are a potent source of arachidonic acid (20:4) metabolites. When macrophages interact with an appropriate stimulus, phospholipase activity is induced, resulting in the liberation of 20:4 from the membrane phospholipid and its quantitative oxygenation via either the lipoxygenase or cyclooxygenase pathways. We have attempted to dissect the molecular events coupling the initial membrane-perturbing signal to the phospholipase activity. Using a variety of stimuli and uncoupling agents we have found that receptor-mediated 20:4 release is triggered by a series of sequential signals, including ligand-receptor binding, receptor clustering, Na+-dependent events, the synthesis of a rapidly turning over protein and finally an influx of Ca2+ into the cell. Bacterial lipopolysaccharides (LPS) are poor triggers of the 20:4 cascade. However, pretreatment of cells with LPS leads to the establishment of a 'primed' or 'intermediate' state which can act synergistically with subsequent signals. Hence, the amount of 20:4 metabolites secreted in response to a variety of triggers is increased 3-10-fold in LPS-primed cells, and the lag phase usually observed in 20:4 secretion disappears. The observations presented suggest a two-stage mode of signalling in the receptor-mediated induction of the 20:4 cascade.