Human neutrophil degranulation responses to nucleotides.
BACKGROUND
Nucleotides have polymorphonuclear neutrophil (PMN)-stimulating actions resembling those of 5-hydroxyicosatetraenoate and its oxo analog, 5-oxoETE. Their effects on degranulation, however, are disputed even though this response may underlie their in vivo toxicity and is well-suited for comparing their mechanism of action with e.g., 5-oxoETE.


METHODS
We measured the direct, synergistic, and cross-desensitizing actions of nine nucleotides and six other stimuli in degranulating unprimed and tumor necrosis factor (TNF)-alpha-primed human PMN.


RESULTS
Nucleotides weakly degranulated unprimed PMN but caused far larger responses in TNF-alpha-primed cells. Their actions, while differing from those of N-formyl-MET-LEU-PHE, platelet-activating factor, leukotriene B4, ionomycin, or dioctanoylglycerol, resembled those of 5-oxoETE. Nucleotides also enhanced PMN degranulation responses to the latter stimuli, particularly 5-oxoETE. Nucleotide degranulating and enhancing potencies were: UTP > or = ATP > or = ATP gamma S > ITP > ADP > 2-MeSATP, nonphosphohydrolyzable analogs lacked activity, and adenosine and AMP blocked PMN degranulation. Finally, nucleotides desensitized degranulation responses to each other but not to 5-oxoETE or other agonists, and 5-oxoETE desensitized to itself but not to nucleotides.


CONCLUSIONS
Nucleotides have intrinsic and synergistic degranulating actions that under appropriate conditions (i.e., in concert with TNF-alpha or 5-oxoETE) are exceedingly prominent. Recognition systems mediating their effects differ from those for various stimuli including 5-oxoETE. These systems likely involve a common "nucleotide" receptor, but studies do not exclude possibilities that other purinergic receptors contribute to their actions.
Department of Medicine, Bowman Gray School of Medicine, Winston-Salem, North Carolina.
J T
JT
O'Flaherty
J F
JF
Cordes
D000227:Adenine Nucleotides / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology*; D004075:Diglycerides / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000227:Adenine Nucleotides; D001095:Arachidonic Acids; D004075:Diglycerides; D010972:Platelet Activating Factor; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; C044295:1,2-dioctanoylglycerol; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D007975:Leukotriene B4; D015759:Ionomycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000241:Adenosine