NPC 15669-MODULATED HUMAN POLYMORPHONUCLEAR NEUTROPHIL FUNCTIONAL RESPONSIVENESS - EFFECTS ON RECEPTOR-COUPLED SIGNAL-TRANSDUCTION

1 The effect of NPC 15669, N-carboxy-L-leucine, N-[(2,7-dimethylfluore n-9-yl)methyl]ester), an inhibitor of human polymorphonuclear neutroph il (PMN) adhesion, on granule exocytosis and the oxidative burst was i nvestigated in PMN activated with receptor-specific pathophysiological stimuli. 2 NPC 15669 caused a concentration-dependent (1-30 mu M) inh ibition of the extracellular release of azurophil (myeloperoxidase) an d specific (vitamin B-12-binding protein) granule constitutents from P MN exposed to N-formyl-methionyl-leucyl-phenylalanine (FMLP), leukotri ene B-4 (LTB(4)), platelet activating factor (PAF), C5a and interleuki n-8 (IL-8). 3 The receptor agonist-triggered PMN oxidative burst, meas ured as superoxide anion (O-2(-) production, was suppressed by NPC 156 69. 4 Phorbol myristate acetate (PMA)-stimulated degranulation and O-2 (-) production were unaffected by NPC 15669. 5 NPC 15669 (0.1-10 mu M) inhibited receptor-triggered inositol 1,4,5-trisphosphate (IP3) produ ction and the IP3-triggered increase in cytosolic-free calcium ([Ca2+] (i)) in FMLP-activated PMN, but not in cells exposed to the other rece ptor agonists. 6 NPC 15669 suppressed FMLP but not PMA-stimulated redi stribution of protein kinase C (PKC) in PMN. 7 The specific binding of [H-3]-FMLP but not [I-125]-C5a to PMN was inhibited by NPC 15669. 8 N PC 15669 suppressed O-2(-) production and the rise in [Ca2+](i) in PMN treated with the guanine nucleotide-binding protein (G-protein) activ ators, sodium fluoride (NaF) and mastoparan, respectively. 9 The resul ts show that NPC 15669 inhibits PMN responsiveness to various receptor agonists, and suggest interference with receptor-coupled signal trans duction in this inflammatory cell at both the receptor and post-recept or level in a stimulus-specific manner.