LONG-CHAIN ACYL-COENZYME-A AND SIGNALING IN NEUTROPHILS - AN INHIBITOR OF ACYL-COENZYME-A SYNTHETASE, TRIACSIN-C, INHIBITS SUPEROXIDE ANIONGENERATION AND DEGRANULATION BY HUMAN NEUTROPHILS

Ligand-initiated activation of neutrophils triggers O-2(-) generation, degranulation, phospholipid remodeling, and release of fatty acids su ch as arachidonate, oleate, and palmitate. Long chain acyl-CoA synthet ase converts free fatty acids to acyl-CoA esters; a role for acyl-CoA esters as positive modulators of neutrophil functions is proposed. Phy siologically relevant concentrations (1-10 mu M) of acyl-CoA esters su ch as palmitoyl-CoA, enhanced O-2(-) 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 O-2(-) generation and degranulation i n a concentration-dependent manner. Triacsin C inhibited O-2(-) genera tion elicited by fMet-Leu-Phe and GTP gamma S in electroporated neutro phils, indicating that acyl-CoA acted downstream from the receptor. Pa lmitoyl CoA reversed the Triacsin C-induced inhibition of O-2(-) gener ation. fMet-Leu-Phe elicited a prompt increase in total long chain acy l CoA esters. Arachidonoyl-CoA and oleoyl-CoA were elevated 5 s after addition of fMet-Leu-Phe, while palmitoyl-CoA was not elevated until 6 0 s. Triacsin C inhibited fMet-Leu-Phe initiated increases in arachido noyl-CoA, oleoyl-CoA, and palmitoyl-CoA. These results suggest a role for acyl CoA esters in regulating activation of O-2(-) generation and degranulation at the G protein or subsequent step(s).