title: Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation.
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.
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Guido A
authors.initials: GA
authors.lastname: Gualdoni
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Lingscheid
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Schmetterer
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Annika
authors.initials: A
authors.lastname: Hennig
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Steinberger
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Zlabinger
mesh_terms: D000818:Animals; D017963:Azithromycin / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D018942:Macrolides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018805:Sepsis / Q000209:etiology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018942:Macrolides; D016328:NF-kappa B; D017963:Azithromycin; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D002118:Calcium