NPC 15669‐modulated human polymorphonuclear neutrophil functional responsiveness: effects on receptor‐coupled signal transduction

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Abstract
1 The effect of NPC 15669, N-carboxy-L-leucine, N-[(2,7-dimethylfluoren-9-yl)methyl]ester), an inhibitor of human polymorphonuclear neutrophil (PMN) adhesion, on granule exocytosis and the oxidative burst was investigated in PMN activated with receptor-specific pathophysiological stimuli. 2 NPC 15669 caused a concentration-dependent (1–30 μm) inhibition of the extracellular release of azurophil (myeloperoxidase) and specific (vitamin B12-binding protein) granule constitutents from PMN exposed to N-formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4), platelet activating factor (PAF), C5a and interleukin-8 (IL-8). 3 The receptor agonist-triggered PMN oxidative burst, measured as superoxide anion (O-2) production, was suppressed by NPC 15669. 4 Phorbol myristate acetate (PMA)-stimulated degranulation and O-2) production were unaffected by NPC 15669. 5 NPC 15669 (0.1–10 μm) inhibited receptor-triggered inositol 1,4,5-trisphosphate (IP3) production and the IP3-triggered increase in cytosolic-free calcium ([Ca2+] I) in FMLP-activated PMN, but not in cells exposed to the other receptor agonists. 6 NPC 15669 suppressed FMLP but not PMA-stimulated redistribution of protein kinase C (PKC) in PMN. 7 The specific binding of [3H]-FMLP but not [125I]-C5a to PMN was inhibited by NPC 15669. 8 NPC 15669 suppressed O-2 production and the rise in [Ca2+]i in PMN treated with the guanine nucleotide-binding protein (G-protein) activators, sodium fluoride (NaF) and mastoparan, respectively. 9 The results show that NPC 15669 inhibits PMN responsiveness to various receptor agonists, and suggest interference with receptor-coupled signal transduction in this inflammatory cell at both the receptor and post-receptor level in a stimulus-specific manner.

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