Abstract
BackgroundIn chronic obstructive pulmonary disease (COPD), lung-infiltrating inflammatory cells secrete proteases and participate in elastin breakdown and genesis of elastin-derived peptides (EP). In the present study, we hypothesized that the pattern of T lymphocytes cytokine expression may be modulated by EP in COPD patients.MethodsCD4+ and CD8+ T-cells, sorted from peripheral blood mononuclear cells (PBMC) collected from COPD patients (n = 29) and controls (n = 13) were cultured with or without EP. Cytokine expression in T-cell phenotypes was analyzed by multicolor flow cytometry, whereas desmosine concentration, a specific marker of elastin degradation, was measured in sera.ResultsCompared with control, the percentage of IL-4 (Th2) producing CD4+ T-cells was decreased in COPD patients (35.3 ± 3.4% and 26.3 ± 2.4%, respectively, p < 0.05), whereas no significant differences were found with IFN-γ (Th1) and IL-17A (Th17). Among COPD patients, two subpopulations were observed based on the percentage of IL-4 (Th2) producing CD4+ T-cells, of which only one expressed high IL-4 levels in association with high levels of desmosine and strong smoking exposure (n = 7). Upon stimulation with VGVAPG, a bioactive EP motif, the percentage of CD4+ T cells expressing IL-4 significantly increased in COPD patients (p < 0.05), but not in controls. The VGVAPG-induced increase in IL-4 was inhibited in the presence of analogous peptide antagonizing VGVAPG/elastin receptor (S-gal) interactions.ConclusionsThe present study demonstrates that the VGVAPG elastin peptide modulates CD4+ T-cells IL-4 production in COPD. Monitoring IL-4 in circulating CD4+ T-cells may help to better characterize COPD phenotypes and could open a new pharmacologic opportunity through CD4+ T-cells stimulation via the VGVAPG/S-gal receptor in order to favor an anti-inflammatory response in those COPD patients.
Highlights
In chronic obstructive pulmonary disease (COPD), lung-infiltrating inflammatory cells secrete proteases and participate in elastin breakdown and genesis of elastin-derived peptides (EP)
We demonstrated that EP modulate interleukin (IL)-4 production by CD4+ T-cells from peripheral blood from COPD patients, and that activating effect of EP on IL-4 production is mediated by S-gal receptor
Type 1 (IFN‐γ), type 2 (IL‐4) and type 17 (IL‐17A) cytokine expression The levels of IFN-γ, IL-4 and IL-17A cytokines expressed by CD4+ and C D8+ T lymphocytes were analyzed in COPD patients n = 29
Summary
In chronic obstructive pulmonary disease (COPD), lung-infiltrating inflammatory cells secrete proteases and participate in elastin breakdown and genesis of elastin-derived peptides (EP). Studies in human with severe α-1 anti-trypsin deficiency [17] and in animal models exposed to proteases [18, 19] suggest that tissue damage associated with COPD partly results from proteolytic breakdown of extracellular matrix proteins by proteases released from lung inflammatory cells [20]. Some of these proteases promote degradation of pulmonary elastin [21]. Increased secretion of desmosine, a specific marker for elastin degradation [22], and elevated levels of soluble elastin peptides (EP) in various biological fluids reflect massive pulmonary elastin breakdown in COPD patients [23, 24]
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