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.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D010740:Phospholipases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D014176:Protein Biosynthesis; D012964:Sodium / Q000378:metabolism
D001095:Arachidonic Acids; D008070:Lipopolysaccharides; D008563:Membrane Lipids; D010743:Phospholipids; D016718:Arachidonic Acid; D012964:Sodium; D010740:Phospholipases; D002118:Calcium