HUMAN NEUTROPHIL DEGRANULATION RESPONSES TO NUCLEOTIDES

BACKGROUND: Nucleotides have polymorphonuclear neutrophil (PMN)-stimul ating actions resembling those of 5-hydroxyicosatetraenoate and its ox o analog, 5-oxoETE. Their effects on degranulation, however, are dispu ted even though this response may underlie their in vivo toxicity and is well-suited for comparing their mechanism of action with e.g., 5-ox oETE. EXPERIMENTAL DESIGN: We measured the direct, synergistic, and cr oss-desensitizing actions of nine nucleotides and six other stimuli in degranulating unprimed and tumor necrosis factor (TNF)-alpha-primed h uman PMN. RESULTS: Nucleotides weakly degranulated unprimed PMN but ca used far larger responses in TNF-alpha-primed cells. Their actions, wh ile differing from those of N-formyl-MET-LEU-PHE, platelet-activating factor, leukotriene B-4, ionomycin, or dioctanoylglycerol, resembled t hose of 5-oxoETE. Nucleotides also enhanced PMN degranulation response s to the latter stimuli, particularly 5-oxoETE. Nucleotide degranulati ng and enhancing potencies were: UTP greater than or equal to ATP grea ter than or equal to ATP gamma S > ITP > ADP > 2-MeSATP, nonphosphohyd rolyzable analogs lacked activity, and adenosine and AMP blacked PMN d egranulation. Finally, nucleotides desensitized degranulation response s to each other but not to 5-oxoETE or other agonists, and 5-oxoETE de sensitized to itself but not to nucleotides.