leukotriene-b4 and 6-anilino-5-8-quinolinedione

Human neutrophils were activated by the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) to produce superoxide (O2-) and to release the primary granule enzyme beta-glucuronidase and the predominantly secondary granule enzyme lysozyme. Pretreatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the secretion of all three substances upon addition of fMLP. The augmentation by GM-CSF was significantly attenuated by the 5-lipoxygenase inhibitor AA861 and by the guanylate cyclase inhibitor LY83583. The secretion induced by fMLP alone was much less affected by either of the two inhibitors. AA861 inhibited leukotriene B4 production in neutrophils primed with GM-CSF and stimulated with fMLP, and LY83583 inhibited GM-CSF-evoked increases of 3',5'-guanosine monophosphate. The data suggest that activation of lipoxygenase and guanylate cyclase is not critical to the fMLP stimulation pathway, but they may be important components of the pathway by which GM-CSF augments neutrophil responses to fMLP. However, AA861 and LY83583 may have important actions in addition to inhibition of 5-lipoxygenase and guanylate cyclase.

Topics: Aminoquinolines; Benzoquinones; Cyclic GMP; Drug Interactions; Granulocyte-Macrophage Colony-Stimulating Factor; Guanylate Cyclase; Humans; Leukotriene B4; Lipoxygenase Inhibitors; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Second Messenger Systems; SRS-A

As auranofin resembles some neutrophil activating sulphur containing compounds, it was decided to investigate whether it had activating effects on neutrophil migration in addition to the published inhibitory effects.. The Boyden chamber assay was used to determine the migration velocity of human neutrophils. The difference between chemotaxis and chemokinesis was established with a chequerboard assay.. Low concentrations of auranofin stimulated human neutrophil migration; concentrations of auranofin higher than 1 mumol/l were inhibitory. Inhibitors of leukotriene formation, or of protein kinase C, had the same effect on auranofin induced potentiation of migration as on fMLP activated migration. Auranofin, at a concentration of 100 nmol/l, caused a transient increase in the cGMP level of neutrophils. The auranofin induced increase in migration was strongly inhibited by methylene blue and by LY83583, two inhibitors of cGMP accumulation.. The auranofin induced enhancement of migration is partly due to a chemokinetic effect, but mainly due to a chemotactic effect. The potentiating effect of auranofin on migration is not specifically due to the ability of the drug to inhibit protein kinase C activity or to generate leukotrienes. These results suggest that the enhancement of neutrophil migration by low levels of auranofin is related to the enhancement of cGMP levels in neutrophils.

Topics: Aminoquinolines; Auranofin; Cell Migration Inhibition; Chemotaxis; Cyclic GMP; Humans; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Protein Kinase C