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Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation.

Gualdoni GA, Lingscheid T, Schmetterer KG, Hennig A, Steinberger P, Zlabinger GJ - Sci Rep (2015)

Bottom Line: Interference with Ca(++)-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide.Azithromycin's inhibiting effects were observed upon LPS, but not upon flagellin, stimulation.We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

ABSTRACT
Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca(++)-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation, and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1α and IL-1β secretion upon LPS stimulation. Interference with Ca(++)-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin's inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1β levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.

No MeSH data available.


Related in: MedlinePlus

Clarithromycin and roxithromycin have no substantial impact on IL-1β secretion.Panel a) and b) show the impact of clarithromycin and roxithromycin, respectively, on LPS or flagellin stimulated IL-1β release by human monocytes. Cells were treated with the indicated concentrations of the drugs and stimulated with either 100 ng/ml LPS or 100 ng/ml flagellin for 20 h. After co-incubation, cell culture supernatants were analysed for the presence of the indicated cytokines by Luminex®. Values are expressed as mean ± SEM from 4 independent experiments.
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f2: Clarithromycin and roxithromycin have no substantial impact on IL-1β secretion.Panel a) and b) show the impact of clarithromycin and roxithromycin, respectively, on LPS or flagellin stimulated IL-1β release by human monocytes. Cells were treated with the indicated concentrations of the drugs and stimulated with either 100 ng/ml LPS or 100 ng/ml flagellin for 20 h. After co-incubation, cell culture supernatants were analysed for the presence of the indicated cytokines by Luminex®. Values are expressed as mean ± SEM from 4 independent experiments.

Mentions: Next, we wanted to find out whether other macrolides have an effect on IL-1β secretion in monocytes as well. For this purpose, we analysed the impact of clarithromycin and roxithromycin on monocytes stimulated with LPS or flagellin. In contrast to azithromycin, neither clarithromycin nor roxithromycin affected IL-1β secretion (Fig. 2a,b, Suppl. Table S1). Induction of the other pro-inflammatory cytokines was also not altered by treatment with these compounds (Suppl. Fig. S2, Suppl. Table S1). These experiments established a unique IL-1β modulating effect of azithromycin among the macrolides studied.


Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation.

Gualdoni GA, Lingscheid T, Schmetterer KG, Hennig A, Steinberger P, Zlabinger GJ - Sci Rep (2015)

Clarithromycin and roxithromycin have no substantial impact on IL-1β secretion.Panel a) and b) show the impact of clarithromycin and roxithromycin, respectively, on LPS or flagellin stimulated IL-1β release by human monocytes. Cells were treated with the indicated concentrations of the drugs and stimulated with either 100 ng/ml LPS or 100 ng/ml flagellin for 20 h. After co-incubation, cell culture supernatants were analysed for the presence of the indicated cytokines by Luminex®. Values are expressed as mean ± SEM from 4 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495566&req=5

f2: Clarithromycin and roxithromycin have no substantial impact on IL-1β secretion.Panel a) and b) show the impact of clarithromycin and roxithromycin, respectively, on LPS or flagellin stimulated IL-1β release by human monocytes. Cells were treated with the indicated concentrations of the drugs and stimulated with either 100 ng/ml LPS or 100 ng/ml flagellin for 20 h. After co-incubation, cell culture supernatants were analysed for the presence of the indicated cytokines by Luminex®. Values are expressed as mean ± SEM from 4 independent experiments.
Mentions: Next, we wanted to find out whether other macrolides have an effect on IL-1β secretion in monocytes as well. For this purpose, we analysed the impact of clarithromycin and roxithromycin on monocytes stimulated with LPS or flagellin. In contrast to azithromycin, neither clarithromycin nor roxithromycin affected IL-1β secretion (Fig. 2a,b, Suppl. Table S1). Induction of the other pro-inflammatory cytokines was also not altered by treatment with these compounds (Suppl. Fig. S2, Suppl. Table S1). These experiments established a unique IL-1β modulating effect of azithromycin among the macrolides studied.

Bottom Line: Interference with Ca(++)-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide.Azithromycin's inhibiting effects were observed upon LPS, but not upon flagellin, stimulation.We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

ABSTRACT
Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca(++)-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation, and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1α and IL-1β secretion upon LPS stimulation. Interference with Ca(++)-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin's inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-κB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1β levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome/IL-1β axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.

No MeSH data available.


Related in: MedlinePlus