Azithromycin inhibits macrophage interleukin-1β production through inhibition of activator protein-1 in lipopolysaccharide-induced murine pulmonary neutrophilia

Bosnar, Martina; Čužić, Snježana; Bošnjak, Berislav; Nujić, Krunoslav; Ergović, Gabrijela; Marjanović, Nikola; Pašalić, Ivanka; Hrvačić, Boška; Polančec, Denis; Glojnarić, Ines; Haber, Vesna Eraković

doi:10.1016/j.intimp.2010.12.010

Cited by 55 publications

(42 citation statements)

References 49 publications

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“…[8][9][10][86][87][88] The mechanism by which azithromycin shifts macrophages from the classically activated (M1) to the alternatively activated (M2) phenotype has not been completely elucidated [89][90][91] ; however, AP-1 activation and impairment of lysosomal functions may be probably involved. 92,93 These immunomodulatory properties contribute to the clinical efficacy of azithromycin in respiratory diseases, 25 whereas their relevance in neurodegenerative conditions has only been partially explored. The immunomodulatory effects of azithromycin result in a significant neuroprotection exerted by an i.p.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Amantea

Certo

Petrelli

et al. 2016

ASSAY and Drug Development Technologies

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Amantea

Certo

Petrelli

et al. 2016

ASSAY and Drug Development Technologies

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“…23,28 Downstream effects include interference with the nuclear expression of activator protein-1 (AP-1) 4 and NFkB. 29 Azithromycin reduces IL-12p40 transcriptional activity by inhibiting the binding of AP-1 to the promoter site.…”

Section: Molecular Mechanisms Of Macrolide Modulation Of Inflammationmentioning

confidence: 99%

“…Azithromycin also blocks interleukin-1b (IL-1b) synthesis by macrophages through its effect on AP-1. 4 These three lymphokines, IL-1b, IL12, and IL23, represent the primary macrophage and dendritic cell lymphokines responsible for the ''deviation'' of T helper cells towards potentially pathogenic phenotypes (see Table 6.3). The non-antimicrobial macrolide CSY0073 (Figure 6.2b) polarises macrophages towards the anti-inflammatory reparative phenotype referred to as M2, alternatively called the alternate activation state, 31 distinguishing them from pro-inflammatory M1 macrophages and from pro-inflammatory ''M17'' macrophages, a new phenotype that is introduced and discussed later in this chapter.…”

Section: Molecular Mechanisms Of Macrolide Modulation Of Inflammationmentioning

confidence: 99%

“…Rather, it appears that the macrolides modify the responsiveness of myeloid derived immune cells, notably neutrophils and macrophages, with the effect of promoting a pro-resolution state that may be observed in the balance of antiand pro-inflammatory cytokines that these cells produce. 4,5 The particular effect of macrolides on neutrophils is enhanced not least in part through their very high partitioning into the phagosomes. Depending on the structure of specific macrolides, and the activation state of the immune cells, the concentration in neutrophils can be up to 1000-fold that of plasma.…”

Section: Introductionmentioning

confidence: 99%

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Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

Burnet

Guse

Gutke

et al. 2014

Macrocycles in Drug Discovery

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Macrolide antibiotics, notably azithromycin, have clinically useful effects in a range of inflammatory diseases and especially those of the lung. Effects include a reduction of inflammatory cytokines, reductions in neutrophil infiltration and potentially a polarisation of infiltrating cells to a pro-resolution phenotype. The mode of action behind this effect is unlikely to be a single interaction and may involve reductions in prostaglandin synthesis via phospholipase inhibition, modulation of NFκB translocation, reduction in IL-8 production and reduction in reflux aspiration to the airways. While some of the clinical effects can be rationalised through antibacterial actions leading to changes in normal flora and reducing Pseudomonads in particular, there is also evidence for effects unrelated to antibacterial actions that appear to relate to reductions in neutrophil activation, potentially related to high accumulation in neutrophil lysosomes. Concerted efforts to improve on these effects have focused on either generating non-antibacterial analogues, or in conjugating anti-inflammatory drugs to the macrolide backbone. Both approaches have provided strong pre-clinical data suggesting that the selective disposition of macrolides to inflamed tissue, as well as their pleiotropic effects on immune cells, contribute to their broad anti-inflammatory effects. The more recent observations of stronger macrolide effects in the context of neutrophil-mediated disease and corresponding effects on IL-17 positive cells in tissue suggest that it may be possible to select patients likely to respond to macrolide therapy. The discovery of non-antibacterial macrolides that preserve this anti-inflammatory effect provides a means to bring these effects more broadly to the clinic without selecting for large-scale resistance to antibacterial macrolides or to other anti-infectives via cross-resistance.

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“…2) (52). The inhibitory effects of azithromycin on neutrophil function in vivo are at least partially due to the modulation of macrophage IL-1β production, probably mediated by the inhibition of activator protein-1 (AP-1) expression (53). These actions ameliorate tissue injury and contribute to improved survival in severe bacterial infections.…”

Section: Pharmacodynamics Of Macrolides: Non-antibiotic Pharmacologicmentioning

confidence: 99%

Macrolides for the treatment of chronic bacterial prostatitis: An effective application of their unique pharmacokinetic and pharmacodynamic profile (Review)

et al. 2011

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Abstract. Chronic bacterial prostatitis (CBP) is a persistent infection of the prostate characterized by poor quality of life mainly due to frequent relapse episodes caused by incomplete eradication of causative pathogens. Aggressive antibacterial therapy is required to attenuate the severe symptoms of CBP and to achieve a permanent cure. Although fluoroquinolones are currently recommended as first-choice agents, macrolide antibiotics are emerging as a noteworthy option for the treatment of CBP. Macrolide antibiotics are characteri zed by an impressive array of distinct pharmacokinetic (PK) and pharmacodynamic (PD) properties. These properties include high intracellular accumulation in phagocytes and at sites of infection, including the prostate; broad antibiotic but also biofilm-inhibiting properties; immunomodulating and inflammation-resolving activities. These features offer particular advantages for the treatment of chronic infections of the prostate gland, which are not easily amenable to drug therapy. Macrolides may be exploited to counteract the unsatisfactory rates of clinical symptom improvement and pathogen eradication. The results of a number of clinical trials support this proposal.

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Azithromycin inhibits macrophage interleukin-1β production through inhibition of activator protein-1 in lipopolysaccharide-induced murine pulmonary neutrophilia

Cited by 55 publications

References 49 publications

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

Macrolides for the treatment of chronic bacterial prostatitis: An effective application of their unique pharmacokinetic and pharmacodynamic profile (Review)

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