1,3-DIOCTANOYLGLYCEROL MODULATES ARACHIDONATE MOBILIZATION IN HUMAN NEUTROPHILS AND ITS INHIBITION BY PGBX - EVIDENCE OF A PROTEIN-KINASE-C-INDEPENDENT ROLE FOR DIACYLGLYCEROLS IN SIGNAL-TRANSDUCTION

Preincubation of human neutrophils with 1-oleoyl-2-acetylglycerol (OAG ) enhances subsequent f-Met-Leu-Phe (fMLP)-stimulated arachidonate mob ilization. We have recently demonstrated that preincubation of neutrop hils with OAG also reverses inhibition of A23187 stimulated [H-3]arach idonate mobilization by the phospholipase A, inhibitors, PGBx and aris tolochic acid. The present study has compared the effects of 1,2-sn-di octanoylglycerol (1,2-diC8) and 1,3-dioctanoylglycerol (1,3-diC8) on t hese cellular events. Dose-dependent priming (ED50 < 2.5 muM) of fMLP- stimulated [H-3]arachidonate mobilization is obtained with both 1,2-di C8 and 1,3-diC8. Both diC8s also enhance fMLP-stimulated synthesis of leukotriene B4, 5-hydroxyeicosatetraenoic acid and platelet-activating factor, and generation of superoxide. Furthermore, both 1,2-diC8 and 1,3-diC8 reverse the effects of PGBx on A23187-stimulated [H-3]arachid onate mobilization and platelet-activating factor synthesis. By contra st, higher concentrations (5-10 muM) of 1,2-diC8, but not 1,3-diC8, di rectly stimulate both [H-3]arachidonate mobilization and superoxide ge neration. Since 1,3-diC8 does not activate protein kinase C (PKC), the se results suggest that PKC is involved in direct activation of neutro phils by diacylglycerols but not in priming. Furthermore, reversal of the inhibitory effects of PGBx by diacylglycerols also appears to invo lve a PKC-independent mechanism.