Inhibition of eicosanoid and PAF formation by dexamethasone in rat inflammatory polymorphonuclear neutrophils may implicate lipocortin 's'.
In polymorphonuclear neutrophils, phospholipase A2 activity is the rate-limiting step for platelet-activating factor (PAF) formation and for the biosynthesis of arachidonic acid derivatives, leukotrienes and prostaglandins. Glucocorticosteroids inhibit phospholipase A2 activity by inducing in target cells the synthesis and release of phospholipase A2 inhibitory proteins named 'lipocortins'. Here, we report that rat pleural inflammatory polymorphonuclear neutrophils, treated with dexamethasone, decrease their production of eicosanoids and PAF. Evidence is presented which may implicate lipocortin 's' in these inhibitions since (i) phospholipase A2 inhibitory proteins are found in the supernatant of dexamethasone-treated cells, (ii) this supernatant inhibits the formation of lipid mediators in untreated cells, inhibition being reversed either by incubating the supernatant with a monoclonal antibody against rat lipocortin or by boiling it and (iii) a 36 kDa lipocortin from mice lungs mimics the effects of dexamethasone when added exogenously on untreated cells. Our results favour the hypothesis that the newly formed lipocortin 's' could be responsible for the antiphospholipase A2 activity of glucocorticosteroids.
Fradin
A
A
Unité de Pharmacologie Cellulaire, INSERM, Institut Pasteur, Paris, France.
Rothhut
B
B
Poincelot-Canton
B
B
Errasfa
M
M
Russo-Marie
F
F
D017302:Annexins; D000001:Calcimycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis*
D017302:Annexins; D006023:Glycoproteins; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003907:Dexamethasone; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone