SIGNAL-TRANSDUCTION PATHWAY IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES FORCHEMOTAXIS INDUCED BY A CHEMOTACTIC FACTOR - DISTINCT FROM THE PATHWAY FOR SUPEROXIDE ANION PRODUCTION

The tyrosine kinase inhibitors erbstatin and herbimycin A inhibited th e chemotactic response to FMLP (2 x 10(-7) M) and the superoxide anion (O-2(-)) production stimulated by FMLP (1 x 10(-6) M) in human polymo rphonuclear leukocytes (PMN) in similar manners. These compounds also inhibited phospholipase D (PLD)-catalyzed breakdown of phosphatidyl ch oline, suggesting a possible link between tyrosine kinase and PLD. In the presence of propranolol (phosphatidic acid (PA) phosphohydrolase i nhibitor), or ethanol, the activation of PLD results in the modulation of PA and/or diglyceride (DG) generation, producing an irregularity i n O-2(-) production. However, PMN motility was not affected in these c onditions. These results suggest that PLD is a downstream effector of FMLP-induced tyrosine kinase activation that leads to activation of th e PMN superoxide release but not to chemotactic migration. In contrast , the tyrosine kinase inhibitors did not inhibit inositol 1,4,5-tripho sphate generation and increase of intracellular concentration of free calcium. Furthermore, a protein kinase C inhibitor, 1-(5-isoquinolines ulfonyl)-2-methylpiperazine dihydrochloride (H-7), did not affect the migration of PMN and the activation of PLD induced by FMLP at concentr ations of less than 50 mu M. These results support the premise that th ere is a specific signaling pathway for chemoattractant-induced PMN lo comotion.