Histone deacetylase activity is decreased in peripheral blood monocytes in patients with COPD

Abstract

BackgroundHistone deacetylase (HDAC) is an enzyme that regulates chromatin structure and inflammatory gene expression. In patients with chronic obstructive pulmonary disease (COPD), while accumulating evidence indicates that the activity of HDAC is decreased in lung tissue alveolar macrophages, HDAC activity in peripheral inflammatory cells has not yet been evaluated in detail.MethodsHDAC activities in peripheral blood mononuclear cells (PBMC) were investigated in patients with stable COPD (n = 26), non-smoking controls (n = 13), and smoking controls (n = 10), respectively. HDAC activity was measured using an HDAC Activity/Inhibitor Screening Assay Kit. Serum interleukine-8 (CXCL8) levels were determined by ELISA techniques. Lung function test was carried out according to the ATS/ERS guidelines.ResultsCompared with healthy non-smokers, HDAC activity in the PBMCs of COPD patients was decreased by 40% (13.06 ± 5.95 vs. 21.39 ± 4.92 (μM/μg), p < 0.001). In patients with COPD, HDAC activity was negatively correlated to smoke intensity (r = -0.867, p < 0.001). In COPD patients who had smoked for more than 40 pack-years, HDAC activity in PBMC was 40% lower than that in COPD patients who had smoked fewer than 40 pack-years.Moreover, serum CXCL8 levels in patients with COPD were significantly higher than that in controls and were negatively correlated to HDAC activities.ConclusionIn patients with COPD, HDAC activity in the PBMCs is lower than that in healthy controls. The reduction of HDAC activity may be associated with smoking exposure through inflammatory pathways.

IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease

“…Moreover, in line with previous studies, 28,30,31 RT-qPCR analysis showed that reduction of HDAC2 content in PBMC samples from patients with COPD induces a dramatically enhanced CXCL8 mRNA transcription in response to LPS compared with that observed in PBMCs from patients with ARF and healthy control subjects (Fig 7, A). Most importantly and further supporting a role for HDAC2 in mediating the suppressive activity of IL-10, a defect in the ability of IL-10 to inhibit LPS-induced CXCL8 transcription was observed (Fig 7, A).…”

“…Most importantly, the latter notion has a relevant translational significance, particularly in the context of COPD. In fact, and in agreement with Chen et al, 28 PBMCs from patients with COPD display consistently reduced HDAC2 gene expression and intracellular protein content, which significantly affects the IL-10 suppressive activity on CXCL8 gene expression. Conversely, PBMCs from healthy subjects or patients affected by respiratory insufficiency consequent to cardiovascular disease did not show any defect in the levels of intracellular HDAC2 and were found to be perfectly responsive to IL-10-mediated transcriptional inhibition of CXCL8 expression.…”

“…37 In fact, the markedly reduced HDAC2 activity and expression in both PBMCs and alveolar macrophages from patients with COPD renders these patients poorly responsive to glucocorticoid therapy. 28,30 Moreover, HDAC2 reduction in patients with COPD strictly correlates with disease severity and increased histone acetylation and inflammatory cytokine gene expression. 38,39 Thus based on our data, it appears that the mechanisms through which IL-10 suppresses CXCL8 transcription closely resemble those used by glucocorticoids because both IL-10 and glucocorticoids converge on the HDAC2 requirement to fulfill their anti-inflammatory actions.…”

“…Because it has been recently shown that the levels and activity of HDAC2 in the lung parenchyma, bronchial biopsy specimens, alveolar macrophages, and peripheral blood monocytes of patients with COPD are greatly reduced compared with those in healthy subjects, [27][28][29][30] we examined whether such HDAC2 reduction impairs the ability of IL-10 to selectively suppress LPS-induced CXCL8 transcription. Thereby PBMCs from 6 patients with COPD (GOLD stage 4), 4 patients with acute respiratory failure (ARF) not consequent to COPD, and 6 healthy control subjects were isolated and incubated for 1 hour with or without LPS in the presence or absence of IL-10.…”

Epigenetic and current treatment approaches in chronic obstructive pulmonary disease

“…Bu durum çevresel etkenlere epigenetik yatkınlığı destekler niteliktedir. Histon asetilason-deasetilasyon dengesinde önemli rol oynayan HDAC2 enzimi KOAH'ta proinflamatuvar sitokinlerin kontrolünde anahtar enzimdir (15). KOAH'ta azalan HDAC aktivitesi, artan NF-κB aktivitesi ve gen ekspresyonu patogenezde rol almaktadır (16,17).…”