Inhibition of O2- generation by dexamethasone is mimicked by lipocortin I in alveolar macrophages.
Glucocorticoids inhibit superoxide (O2-) generation by phagocytes through a mechanism that remains unclear. We investigated this effect by using dexamethasone on guinea pig alveolar macrophages. O2- generation was induced either by the calcium ionophore A23187, a potent stimulus of phospholipase A2, or by the protein kinase C activator, phorbol myristate acetate (PMA). Dexamethasone inhibited O2- generation initiated by A23187 by 50-55%. This inhibition required: (a) more than 45 min incubation and was maximal after 2 h; (b) glucocorticoid receptor occupancy; and (c) protein synthesis. The inhibitory effect of dexamethasone could not be explained by an interaction with the respiratory burst enzyme NADPH oxidase since O2- generation was only weakly affected upon PMA stimulation. Lipocortin I, a glucocorticoid inducible and phospholipase A2 inhibitory protein, inhibited O2- generation initiated by A23187 but failed to modulate the respiratory burst activated by PMA. These results were obtained with lipocortin I purified from mouse lungs, human blood mononuclear cells, and with human recombinant lipocortin I. We propose that lipocortin I is capable of inhibiting the activation of NADPH oxidase only when membrane signal transduction involves phospholipase A2. By mimicking the effect of dexamethasone, lipocortin I may extend its potential anti-inflammatory action to the partial control of the formation of oxygen reactive species by phagocytes.
Maridonneau-Parini
I
I
Unité de Pharmacologie Cellulaire associée Unité Institut Nationale de la Santé et de la Recherche Medicale U285, Paris, France.
Errasfa
M
M
Russo-Marie
F
F
D000818:Animals; D017302:Annexins; D000001:Calcimycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D006023:Glycoproteins / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000494:pharmacology; D011650:Pulmonary Alveoli; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D017302:Annexins; D006023:Glycoproteins; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D013481:Superoxides; D000001:Calcimycin; D003907:Dexamethasone; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone