Immunomodulatory effects of azithromycin on the establishment of lipopolysaccharide tolerance in mice

• Published in: International immunopharmacology 2013-03, Vol.15 (3), p.498-504
• Main Authors: Bosnar, Martina, Dominis-Kramarić, Miroslava, Nujić, Krunoslav, Stupin Polančec, Darija, Marjanović, Nikola, Glojnarić, Ines, Eraković Haber, Vesna
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - administration & dosage; Azithromycin - administration & dosage; Cells, Cultured; Chemokine CCL5 - blood; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; IL-10; IL-1ra; Immunomodulation - drug effects; Inflammation Mediators - blood; Interleukin 1 Receptor Antagonist Protein - blood; Interleukin-10 - blood; Lipopolysaccharides - immunology; Macrolide; Male; Mice; Mice, Inbred C57BL; Sepsis; Survival; TNFα; Tumor Necrosis Factor-alpha - blood
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2013.02.011

Recent reports suggest that azithromycin can shift macrophage polarization towards the alternatively activated M2 phenotype. In order to investigate its immunomodulatory activity in vivo, the influence of azithromycin on survival and cytokine production was assessed in the LPS tolerance model which is characterized by an M2 skewed response. For induction of tolerance, mice received an intraplantar injection of 30μg LPS, 24h prior to intravenous challenge with 350μg LPS. Azithromycin (100mg/kg) was administered orally, 2h before LPS application. Influence of treatment on survival and cytokine concentration in serum was monitored. Azithromycin alone, instead of LPS, could not induce an LPS tolerant state. However, when administered before LPS priming it significantly increased survival, which was enhanced by concomitant azithromycin before LPS challenge. Azithromycin had no effect on survival when administered only prior to the LPS challenge. Tolerance induction by LPS priming was associated, upon LPS challenge, with decreased serum concentrations of pro-inflammatory cytokines, TNFα, IL-12p40 and CCL5, and increased serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra. Azithromycin treatment, prior to LPS priming, further reduced serum TNFα and CCL5, yielding the greatest inhibition when the macrolide was also given prior to LPS challenge. Serum concentrations of the anti-inflammatory cytokines, IL-10 and IL-1ra, were unchanged following azithromycin treatment. In summary, we have confirmed the immunomodulatory activity of azithromycin, as reflected in its ability to augment tolerance induction to LPS, promoting increased survival and reduced pro-inflammatory cytokine production, without affecting overt inflammation to LPS or anti-inflammatory cytokine production. ► LPS tolerance model is characterized by an M2 skewed response ► Azithromycin augmented tolerance induction to LPS. ► Azithromycin reduced serum concentrations of pro-inflammatory cytokines TNFα and CCL5. ► Concentrations of anti-inflammatory cytokines, IL-10 and IL-1ra, were unchanged following azithromycin treatment.