32 research outputs found
Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation
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
CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages : Antiviral Effects of mTOR Inhibitors
Human cytomegalovirus (CMV) remains one of the
most important pathogens following solid-organ
transplantation. Mounting evidence indicates that
mammalian target of rapamycin (mTOR) inhibitors
may decrease the incidence of CMV infection in solid-
organ recipients. Here we aimed at elucidating the
molecular mechanisms of this effect by employing
a human CMV (HCMV) infection model in human
macrophages, since myeloid cells are the principal
in
vivo
targets of HCMV. We demonstrate a highly di-
vergent host cell permissiveness for HCMV with opti-
mal infection susceptibility in M2 but not M1 polarized
macrophages. Employing an ultrahigh purified HCMV
stock we observed rapamycin-independent viral entry
and induction of IFN-b transcripts, but no proinflam-
matory cytokines or mitogen-activated protein kinases
and mTOR activation early after infection. However,
in the late infection phase, sustained mTOR activa-
tion was observed in HCMV-infected cells and was
required for efficient viral protein synthesis including
the viral late phase proteins pUL-44 and pp65. Accord-
ingly, rapamycin strongly suppressed CMV replication
3 and 5 days postinfection in macrophages. In conclu-
sion, these data indicate that mTOR is essential for
virus replication during late phases of the viral cycle in
myeloid cells and might explain the potent anti-CMV
effects of mTOR inhibitors after organ transplantatio