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
