Regulation of human neutrophil functions by adenine nucleotides.
Previous work has shown that platelet-derived adenine nucleotides modulate neutrophil superoxide anion (O2-) generation. Additional studies were undertaken to characterize the effects of authentic adenosine (ADO) and its nucleotide derivatives on the inflammatory functions of human neutrophils. Stimulus-specific inhibition of neutrophil O2- generation by ADO in response to FMLP was verified. In addition, the ability of ATP, ADP, and AMP to limit neutrophil O2- generation induced by FMLP (0.2 to 0.5 microM) was demonstrated. The concentration producing 50% inhibition for nucleotide inhibition of neutrophil O2- generation was in the rank order of ADO (0.1 microM) less than AMP (0.5 microM) less than ADP less than or equal to ATP (5 microM). Guanine and inosine nucleotides (0.01 to 100 microM) did not inhibit FMLP-stimulated neutrophil O2- generation. Neutrophil degranulation in response to FMLP was only modestly inhibited by adenine nucleotides and ADO. Adenosine and ADP failed to affect chemotaxis of neutrophils stimulated with FMLP. The inability of non-metabolizable analogs to mimic the inhibitory effects of authentic ATP or ADP on the neutrophil O2- response suggested that metabolism of added nucleotides is necessary for their effectiveness. Both TLC and HPLC confirmed that ATP and ADP were converted to AMP and ADO after their incubation with unstimulated or FMLP-activated neutrophils. The addition of adenosine deaminase to neutrophil reaction mixtures in which conversion of added nucleotides was apparent removed detectable ADO but failed to completely abrogate the inhibition of neutrophil O2- generation by accumulated AMP. The kinetics of inhibition of FMLP-induced neutrophil O2- generation by ATP and ADP also indicated that conversion of these nucleotides to ADO and/or AMP may be essential for their ability to reduce neutrophil responses.
McGarrity
S T
ST
Department of Microbiology, St. Louis University School of Medicine, MO 63104.
Stephenson
A H
AH
Webster
R O
RO
D000227:Adenine Nucleotides / Q000494:pharmacology / Q000502:physiology*; D000241:Adenosine / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D002474:Cell-Free System; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011685:Purine Nucleotides / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000227:Adenine Nucleotides; D011685:Purine Nucleotides; D013481:Superoxides; D000249:Adenosine Monophosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000243:Adenosine Deaminase; D000241:Adenosine