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Comparison of various macrolides on stimulation of human neutrophil degranulation in vitro
H Abdelghaffar1, D Vazifeh, M T Labro
1INSERM U294, Service d'Hématologie et d'Immunologie Biologiques, CHU Xavier Bichat, Paris, France.
Abstract:
Macrolide antibiotics are taken up and concentrated by host cells, particularly phagocytes, and are likely candidates to modify cell functions. In this study, we extended our previous work concerning the effect of three 14-membered-ring macrolides (dirithromycin, erythromycin and erythromycylamine) on human neutrophil exocytosis, and found that three other erythromycin A derivatives (roxithromycin, clarithromycin and the azalide, azithromycin) also triggered neutrophil degranulation in a time- and concentration-dependent manner. After 30 min of incubation, the correlation coefficients for concentration-dependence for roxithromycin were 0.885, 0.739 and 0.750 (P < 0.005) and for clarithromycin were 0.795, 0.599, 0.733 (P < 0.02), respectively, for lysozyme, beta-glucuronidase and lactoferrin release. Although the underlying mechanism was not elucidated, these and previous data suggest that intracellular accumulation is a prerequisite. Furthermore, comparison of the characteristics of macrolide-induced exocytosis with those of exocytosis triggered by the synthetic chemotactic stimulus FMLP suggested that different mechanisms are involved. In keeping with this possibility, we showed that combined treatment (macrolides plus FMLP) resulted in totally additive exocytosis of azurophilic but not specific granules. The clinical relevance of our data remains to be ascertained.
Insights
Macrolide antibiotics, including newer erythromycin derivatives like roxithromycin and clarithromycin, stimulate human neutrophil degranulation. This effect, dependent on concentration and time, suggests intracellular accumulation is key and differs from FMLP-induced mechanisms.
Area of Science:
- Immunology
- Pharmacology
Background:
- Macrolide antibiotics accumulate in host cells, especially phagocytes.
- Previous studies indicated macrolides affect neutrophil functions.
Purpose of the Study:
- To investigate the effect of additional macrolides on human neutrophil exocytosis.
- To compare macrolide-induced exocytosis with FMLP-triggered pathways.
Main Methods:
- Incubation of human neutrophils with various macrolides (roxithromycin, clarithromycin, azithromycin).
- Measurement of neutrophil degranulation markers (lysozyme, beta-glucuronidase, lactoferrin).
- Comparison with formyl-methionyl-leucyl-phenylalanine (FMLP) stimulation.
Main Results:
- Roxithromycin and clarithromycin induced neutrophil degranulation in a time- and concentration-dependent manner.
- Significant correlations observed for release of lysozyme, beta-glucuronidase, and lactoferrin.
- Macrolide-induced exocytosis appears distinct from FMLP pathways, with additive effects on specific granule release.
Conclusions:
- Several macrolides trigger human neutrophil degranulation, likely requiring intracellular accumulation.
- The mechanism differs from FMLP-induced degranulation, suggesting distinct cellular signaling pathways.
- Clinical significance requires further investigation.