Inhibition by Erythromycin of Superoxide Anion Production by Human Polymorphonuclear Leukocytes through the Action of Cyclic AMP-Dependent Protein Kinase

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Abstract
The long-term low-dose administration of erythromycin is effective in treating chronic inflammatory diseases of the lower respiratory tract. The aim of this study was to clarify the mechanism for this therapeutic effect of erythromycin. We measured its effect on the production of superoxide anion (O2-) by polymorphonuclear leukocytes (PMN) that was induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) or by phorbol myristate acetate (PMA). 25 μM erythromycin inhibited fMLP-induced O2- production by about 50%, but not PMA-induced O2- production. Moreover, this inhibition was overcome by adding an inhibitor of cyclic AMP-dependent protein kinase (PKA), H-89. The fMLP-induced O2- production was also inhibited by isoproterenol, a β-adrenergic agonist, and by dibutyryl cyclic AMP, a cell membrane permeating analogue of cyclic AMP. The inhibition was also overcome by the addition of H-89. Therefore, the effect of erythromycin seemed to be, in part, mediated through the activation of PKA. The inhibition by erythromycin of O2- generation by PMN may contribute to the beneficial effect of this drug in treating chronic respiratory diseases.

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