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
H. Abdelghaffar et al., 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, The Journal of immunology, 159(8), 1997, pp. 3995-4005
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.