Long chain acyl coenzyme A and signaling in neutrophils. An inhibitor of acyl coenzyme A synthetase, triacsin C, inhibits superoxide anion generation and degranulation by human neutrophils.
Ligand-initiated activation of neutrophils triggers O2- generation, degranulation, phospholipid remodeling, and release of fatty acids such as arachidonate, oleate, and palmitate. Long chain acyl-CoA synthetase converts free fatty acids to acyl-CoA esters; a role for acyl-CoA esters as positive modulators of neutrophil functions is proposed. Physiologically relevant concentrations (1-10 microM) of acyl-CoA esters such as palmitoyl-CoA, enhanced O2- generation triggered by fMet-Leu-Phe or guanosine 5'-O-(thiotriphosphate) (GTP gamma S) but did not act as a trigger per se. Triacsin C, an inhibitor of acyl-CoA synthetase, inhibited fMet-Leu-Phe-elicited O2- generation and degranulation in a concentration-dependent manner. Triacsin C inhibited O2- generation elicited by fMet-Leu-Phe and GTP gamma S in electroporated neutrophils, indicating that acyl-CoA acted downstream from the receptor. Palmitoyl-CoA reversed the Triacsin C-induced inhibition of O2- generation. fMet-Leu-Phe elicited a prompt increase in total long chain acyl-CoA esters. Arachidonoyl-CoA and oleoyl-CoA were elevated 5 s after addition of fMet-Leu-Phe, while palmitoyl-CoA was not elevated until 60 s. Triacsin C inhibited fMet-Leu-Phe-initiated increases in arachidonoyl-CoA, oleoyl-CoA, and palmitoyl-CoA. These results suggest a role for acyl-CoA esters in regulating activation of O2- generation and degranulation at the G protein or subsequent step(s).
Korchak
H M
HM
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia 19104.
Kane
L H
LH
Rossi
M W
MW
Corkey
B E
BE
D000214:Acyl Coenzyme A / Q000097:blood*; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors*; D003571:Cytochalasin B / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000097:blood*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology*
D000214:Acyl Coenzyme A; D014226:Triazenes; D013481:Superoxides; D003571:Cytochalasin B; D015759:Ionomycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C034613:triacsin C; D003066:Coenzyme A Ligases; D013755:Tetradecanoylphorbol Acetate