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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

Azithromycin affects IL-1β secretion in vivo.Panel a)-c) show the impact of azithromycin treatment on cytokine levels in a murine LPS-sepsis model. Female C57BL/6 (n = 10 mice per group) were injected with 50 mg/kg BW azithromycin or placebo and subsequently were injected with 2.5 mg/kg BW LPS. Serum samples were obtained 6 h after injection and cytokines were measured by Luminex®. Results are depicted as mean ± SEM.
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f5: Azithromycin affects IL-1β secretion in vivo.Panel a)-c) show the impact of azithromycin treatment on cytokine levels in a murine LPS-sepsis model. Female C57BL/6 (n = 10 mice per group) were injected with 50 mg/kg BW azithromycin or placebo and subsequently were injected with 2.5 mg/kg BW LPS. Serum samples were obtained 6 h after injection and cytokines were measured by Luminex®. Results are depicted as mean ± SEM.

Mentions: In order to further substantiate our findings, we assessed the impact of azithromycin on cytokine induction in a murine model of LPS sepsis. In line with our in vitro observations, we found a selective down-modulation of IL-1β levels in the course of endotoxin sepsis whereas other pro-inflammatory cytokines remained unaffected by the treatment (Fig. 5a–c). Although the results did not reach statistical significance, probably due to the high variability in this model, the specificity of azithromycin’s effects on cytokine production is remarkable. These findings substantiate the potential impact of our findings for an in vivo situation which might be of relevance in clinical conditions as well.


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)

Azithromycin affects IL-1β secretion in vivo.Panel a)-c) show the impact of azithromycin treatment on cytokine levels in a murine LPS-sepsis model. Female C57BL/6 (n = 10 mice per group) were injected with 50 mg/kg BW azithromycin or placebo and subsequently were injected with 2.5 mg/kg BW LPS. Serum samples were obtained 6 h after injection and cytokines were measured by Luminex®. Results are depicted as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Azithromycin affects IL-1β secretion in vivo.Panel a)-c) show the impact of azithromycin treatment on cytokine levels in a murine LPS-sepsis model. Female C57BL/6 (n = 10 mice per group) were injected with 50 mg/kg BW azithromycin or placebo and subsequently were injected with 2.5 mg/kg BW LPS. Serum samples were obtained 6 h after injection and cytokines were measured by Luminex®. Results are depicted as mean ± SEM.
Mentions: In order to further substantiate our findings, we assessed the impact of azithromycin on cytokine induction in a murine model of LPS sepsis. In line with our in vitro observations, we found a selective down-modulation of IL-1β levels in the course of endotoxin sepsis whereas other pro-inflammatory cytokines remained unaffected by the treatment (Fig. 5a–c). Although the results did not reach statistical significance, probably due to the high variability in this model, the specificity of azithromycin’s effects on cytokine production is remarkable. These findings substantiate the potential impact of our findings for an in vivo situation which might be of relevance in clinical conditions as well.

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