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Biochem Pharmacol. 1997 Jun 15;53(12):1929-36.

Effect of wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) on N-formyl-methionyl-leucyl-phenylalanine-induced phospholipase D activation in differentiated HL60 cells: possible involvement of phosphatidylinositol 3-kinase in phospholipase D activation.

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  • 1Department of Pharmacy, Gifu University Hospital, Japan.


Phospholipase D (PLD) plays an important role in neutrophil activation. However, despite various proposed mechanisms, its detailed regulatory mechanism is not fully understood. The functional coupling between phosphatidylinositol 3-kinase (PI 3-kinase) and PLD was investigated in N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated human promyelocytic leukemia HL60 cells, using wortmannin, a fungal metabolite that is known as a selective inhibitor for phosphatidylinositol 3-kinase. Treatment of cells with this drug inhibited the formation of both phosphatidylinositol 3,4,5-trisphosphate (PIP3), a product of PI 3-kinase, and phosphatidylbutanol (PBut), the specific product of transphosphatidylation due to PLD in the presence of butanol, with similar concentration dependence (IC50 = 30-70 nM). Another PI 3-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) also inhibited PBut formation in a concentration-dependent manner. However, wortmannin failed to inhibit phorbol 12-myristate 13-acetate-induced PLD activation in whole cells and membrane PLD activity in an in vitro assay system, indicating that inhibition of fMLP-induced PLD activation by wortmannin was not due to its direct effect on PLD activity. These results suggest that a major part of inhibition of PLD activation by wortmannin might be mediated through its effect on PI 3-kinase.

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