CELLULAR-REGULATION OF ARACHIDONATE MOBILIZATION AND METABOLISM

Synthesis of eicosanoids is initiated by signal transduction cascades which result in the hydrolysis of free arachidonic acid from membrane phospholipids. Both a cytosolic 85 kDa and a nonpancreatic 14 kDa PLA2 may contribute to cellular arachidonate mobilization. In many cells, agonist-stimulated fatty acid release is dependent upon increases in i ntracellular free calcium and is enhanced by pretreatment with agents such as phorbol esters and soluble diglycerides. The response is speci fic for arachidonate and structurally similar polyunsaturated fatty ac ids containing a cis 5, 6 double bond. DMSO-differentiation of U937 ce lls markedly enhances the A23187-stimulated release of [H-3]arachidona te, which appears to be coupled to differentiation-induced enhancement of capacitance calcium entry, Although both phorbol esters and solubl e diglycerides enhance subsequent fMLP or A23187-stimulated arachidona te release in human neutrophils, several lines of evidence indicate th at the effects of oleoylacetylglycerol and 1,2-dioctanoylglycerol are protein kinase C-independent. Soluble diglycerides, but not phorbol es ters, enhance the coupling of arachidonate mobilization to subsequent leukotriene B-4, synthesis, Further studies will be required to elucid ate the mechanisms which regulate activation of cellular phospholipase s and subsequent synthesis.