Comparison of various macrolides on stimulation of human neutrophil degranulation in vitro

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.

Leukotriene B4 Induces Release of Antimicrobial Peptides in Lungs of Virally Infected Mice

“…Cytochalasin B was used as a priming agent for neutrophil degranulation and has no significant effect on cell activation (40,41). After cytochalasin treatment, cells were stimulated or not with LTB 4 for 30 min.…”

Open label trial of oral clarithromycin in active Crohn’s disease

“…Clarithromycin also suppresses the synthesis of tumour necrosis factor α, interleukin 1α, IL‐1 β, IL‐1 receptor antagonist, and granulocyte‐macrophage colony‐stimulating factor in LPS primed monocytes in a concentration‐dependent manner whilst IL‐10 synthesis is increased 28 . Neutrophil degranulation is also triggered in a time and concentration dependent manner by intracellular clarithromycin 29 whereas erythromycin (but not clarithromycin) has been shown to inhibit neutrophil superoxide production 30 . These properties of enhancing phagocyte function may be particularly important because there is a body of evidence suggesting that neutrophil function is impaired in Crohn’s disease 31 –33 and the ability of clarithromycin to improve phagocyte function may contribute to its beneficial effect on Crohn’s disease.…”

Immunomodulatory Effects of Macrolide Antibiotics – Part 1: Biological Mechanisms

“…Upon activation, neutrophils release granules containing cytotoxic enzymes, such as elastase, a process called neutrophil degranulation or exocytosis. In general, macrolides seem to stimulate exocytosis, which may result in enhanced antibactericidal activity [1,73,74,75,76]. …”