title: Immunomodulatory effects of azithromycin on the establishment of lipopolysaccharide tolerance in mice.
abstract: 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 30 μg LPS, 24 h prior to intravenous challenge with 350 μg LPS. Azithromycin (100 mg/kg) was administered orally, 2 h 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.
authors: GlaxoSmithKline Research Centre Zagreb Limited, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. martina.bosnar@glpg.com
authors: Martina
authors: M
authors: Bosnar
authors: Miroslava
authors: M
authors: Dominis-Kramarić
authors: Krunoslav
authors: K
authors: Nujić
authors: Darija
authors: D
authors: Stupin Polančec
authors: Nikola
authors: N
authors: Marjanović
authors: Ines
authors: I
authors: Glojnarić
authors: Vesna
authors: V
authors: Eraković Haber
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D017963:Azithromycin / Q000008:administration & dosage*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000900:Anti-Bacterial Agents; D018946:Chemokine CCL5; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017963:Azithromycin