Azithromycin modulates release of steroid-insensitive cytokines from peripheral blood mononuclear cells of patients with chronic obstructive pulmonary disease

Introduction: Oxidative stress reduces responsiveness of peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) to the anti-inflammatory effects of glucocorticoids (GCs). Azithromycin was shown to modulate corticosteroid resistance mechanisms in COPD patients. However, its ability to enhance anti-inflammatory properties of GCs on the production of cytokines by PBMCs has not well been elucidated.

Material and methods: Heparinised blood was collected from 27 patients with COPD. Phytohaemagglutinin-induced release of pro-inflammatory mediators from PBMCs and production of intracellular cytokines by CD4+ and CD8+ T cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in the presence or absence of 10 μg/mL azithromycin and 10 nM budesonide were determined using enzyme linked immunosorbent assay and flow cytometry.

Results: Azithromycin decreased the secretion of interleukin (IL) 4, IL-5, IL-13, and IL-17A from PBMCs, as well as the production of IL-4 and IL-8 by CD4+ and CD8+ T cells. The combination of azithromycin and budesonide suppressed inflammatory response by inhibition of IL-4, IL-5, IL-8, IL-13, IL-17A, IL-33, thymic stromal lymphopoietin (TSLP), macrophage migration inhibitory factor (MIF) release from PBMCs and by reduction of the percentage of IL-4-, IL-8-, interferon γ- and tumor necrosis factor a-expressing CD4+ and CD8+ T cells. The inhibitory effect of azithromycin combined with budesonide on IL-4, IL-5, IL-8, IL-17A, TSLP production by PBMCs, as well as IL-4 and IL-8 production by T helper cells and cytotoxic T lymphocytes was significantly greater than the effect of budesonide alone.

Conclusions: Azithromycin in combination with budesonide enhances GC properties by inhibiting synthesis of pro-inflammatory cytokines in blood cells of COPD patients.