Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation.
15(S)-Hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid (15-HETE) exerted a time- and concentration-dependent inhibition of superoxide anion (O2-) production and exocytosis of both azurophil and specific granule constituents from human polymorphonuclear neutrophils (PMN) stimulated with the receptor-specific agonists, N-formylmethionylleucylphenylalanine (FMLP), platelet-activating factor, and leukotriene B4, but not that elicited by phorbol 12-myristate 13-acetate. 15-HETE did not alter the binding of FMLP to its specific receptors on PMN but, rather, appeared to interfere with a subsequent process in signal transduction. Receptor-coupled production of inositol 1,4,5-trisphosphate (InsP3) and increases in cytosolic free calcium elicited with FMLP, platelet-activating factor, and leukotriene B4 were suppressed by 15-HETE. 15-HETE did not, however, inhibit the mobilization of 45Ca from intracellular stores elicited by the addition of InsP3 to permeabilized PMN. 15-HETE suppressed O2- production and increases in intracellular [Ca2+] induced when cell-surface receptors were bypassed and the PMN were activated directly by the guanine nucleotide-binding protein (G protein) activators aluminum fluoride (AlF4-) and mastoparan. 15-HETE, however, did not perturb all G protein functions because cAMP production in FMLP-activated PMN was essentially unaffected by 15-HETE. These data support the proposition that 15-HETE modulates receptor-triggered activation of PMN either by uncoupling G protein stimulation of phospholipase C or by directly inhibiting phospholipase C, thus inhibiting the InsP3-dependent rise in intracellular [Ca2+] that is prerequisite for PMN responsiveness to receptor agonists.
Department of Hypersensitivity Diseases Research, Upjohn Co., Kalamazoo, MI 49001.
R J
RJ
Smith
J M
JM
Justen
E G
EG
Nidy
L M
LM
Sam
J E
JE
Bleasdale
D000535:Aluminum / Q000494:pharmacology; D017607:Aluminum Compounds; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D002462:Cell Membrane / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D005459:Fluorides / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D010455:Peptides; D011493:Protein Kinase C / Q000502:physiology; D016897:Respiratory Burst; D015398:Signal Transduction; D014862:Wasp Venoms / Q000494:pharmacology
D017607:Aluminum Compounds; D006893:Hydroxyeicosatetraenoic Acids; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014862:Wasp Venoms; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009240:N-Formylmethionine Leucyl-Phenylalanine; C037500:mastoparan; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D015544:Inositol 1,4,5-Trisphosphate; D000535:Aluminum; D000242:Cyclic AMP; D011493:Protein Kinase C; D020558:GTP Phosphohydrolases; D005459:Fluorides; D002118:Calcium; C032311:aluminum fluoride