ERYTHROMYCIN A-DERIVED MACROLIDES MODIFY THE FUNCTIONAL ACTIVITIES OFHUMAN NEUTROPHILS BY ALTERING THE PHOSPHOLIPASE D-PHOSPHATIDATE PHOSPHOHYDROLASE TRANSDUCTION PATHWAY - L-CLADINOSE IS INVOLVED BOTH IN ALTERATIONS OF NEUTROPHIL FUNCTIONS AND MODULATION OF THIS TRANSDUCTIONALPATHWAY

All erythromycin A derivatives, irrespective of the size of the lacton e ring and the nature of the substituent, inhibit oxidant production b y neutrophils and promote their degranulation. We demonstrate in this study that the L-cladinose at position 3 of the lactone ring is a key structure in the modulation of these two neutrophil functions, suggest ing that this sugar (alone or combined with a lactone structure) inter feres with cell target(s) involved in both oxidant production and exoc ytosis, Taking roxithromycin as an example of erythromycin A derivativ es, we also found that these molecules interfered with the phospholipa se D (PLD)-phosphatidate phosphohydrolase pathway in two ways, In reon stimulated neutrophils, roxithromycin and all L-cladinose-bearing mole cules activated PLD, as reflected by 1-O-[H-3]alkyl-2-acyl-phosphatidy l-ethanol production. In addition, these drugs induced an accumulation of 1-O-[H-3]alkyl-2-acyl-phosphatidic acid (PA), but not 1-O-[H-3]alk yl-2-acylglycerol. PA accumulation seems to be involved in the inducti on of exocytosis by macrolides, as the roxithromycin-induced release o f granular enzymes was impaired strongly in the presence of ethanol, B y contrast, in stimulated neutrophils, roxithromycin inhibited PLD act ivity and totally impaired 1-O-[H-3]alkyl-2-acylglycerol production. T he inhibition of diglyceride production by roxithromycin (not its desc ladinosyl derivative) could explain its inhibitory effect on oxidant p roduction, The relevance of our data to the clinical situation, partic ularly the anti-inflammatory activity of these drugs, requires further investigation.