Functional coupling and differential regulation of the phospholipase A₂-cyclooxygenase pathways in inflammation

Prostaglandins generated by the phospholipase A₂ (PLA₂)/cyclooxygenase (COX) pathway are well known to mediate diverse intracellular and extracellular effects that regulate mammalian development, vascular function, renal physiology, parturition, and immune responses to infection or wounding. In immune-mediated diseases and in certain cancers, this pathway is aberrantly upregulated and excessive prostaglandin production contributes to the pathology. It is now known that there are two isoforms of COX and multiple secreted and intracellular PLA₂ enzymes. The use of isoform- specific inhibitors, coupled with antisense and in vivo gene deletion experiments, has identified independent pathways of arachidonic acid metabolism, which are differentially regulated at the levels of gene expression, protein phosphorylation, and cellular localization. There is cross-talk between the pathways at the level of PLA₂ and substrate supply to the two isoforms of COX is apparently compartmentalized. Knockout studies have shown that the two COX isoforms play independent roles in immediate and delayed agonist-induced prostaglandin synthesis. Cytosolic PLA₂-α is essential for both responses. Inducible secreted forms of PLA₂ are, as yet, not essential for either response with the exception of the in vitro murine mast cell immediate response and instances of murine macrophage prostaglandin synthesis. These enzymes amplify the delayed response and are likely to modulate the severity of immune-mediated diseases.