Inhibition of formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst in human neutrophils by adrenaline: inhibition of Phospholipase A2 activity but not p47phox phosphorylation and translocation.
The polymorphonuclear neutrophil (PMN)-respiratory burst plays a key role in host defense and inflammatory reactions. Modulation of this key neutrophil function by endogenous agents and the mechanisms involved are poorly understood. This study was designed to analyze the mechanisms involved in the effect of adrenaline on neutrophil superoxide anions production. Using the superoxide dismutase (SOD)-inhibitable cytochrome c reduction assay, we report here that the beta-adrenergic agonist, adrenaline at physiologic concentrations (5-100 nM) inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated but not phorbol-myristate-acetate (PMA)-stimulated PMN superoxide anion production. The inhibitory effect of adrenaline runs in parallel with an increase in intracellular levels of cAMP which was reversed by the protein kinase A (PKA) inhibitor H-89, suggesting a role for PKA in mediating the inhibitory effect of adrenaline on fMLP-induced superoxide production. Adrenaline at physiological concentrations did not inhibit the fMLP-stimulated membrane translocation of the NADPH oxidase components p47phox and p67phox, nor the fMLP-stimulated phosphorylation of p47phox. However, adrenaline strongly depressed the activity of the cytosolic isoform of Phospholipase A(2) (cPLA(2)). We suggest that adrenaline inhibits fMLP induced superoxide production upstream of the NADPH oxidase via a mechanism involving PKA and cPLA(2).
O'Dowd
Yvonne M
YM
Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, 4, Dublin, Ireland.
El-Benna
Jamel
J
Perianin
Axel
A
Newsholme
Philip
P
D001692:Biological Transport; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004537:Eicosanoic Acids / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors*; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016897:Respiratory Burst / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides
D004537:Eicosanoic Acids; D007546:Isoquinolines; D010750:Phosphoproteins; D013449:Sulfonamides; C079789:neutrophil cytosol factor 67K; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D017868:Cyclic AMP-Dependent Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C094477:arachidic acid; D004837:Epinephrine