Abstract
BackgroundHistone acetyltransferases (HAT) and histone deacetylases (HDAC) are enzymes that upregulate and down-regulate pro-inflammatory gene transcription respectively. HDAC2 is required by corticosteroids to switch off activated inflammatory genes and is reduced in lung macrophages in COPD. We have shown that COPD patients have increased steroid resistant CD28null (senescent) pro-inflammatory T and NKT-like peripheral blood cells (particularly CD8+ subsets) and we hypothesized that these changes would be associated with a loss of HDAC2 from these senescent pro-inflammatory lymphocytes.MethodsBlood was collected from 10 COPD and 10 aged-matched controls. Intracellular pro-inflammatory cytokines, IFNγ and TNFα, and expression of CD28, HDAC2 and HAT, were determined in lymphocyte subsets in the presence of ± 5 mg/ml theophylline (HDAC2 activator), 10 μM prednisolone and 2.5 ng/ml cyclosporine A (immunosuppressant), using flow cytometry.ResultsThere was a loss of HDAC2 from CD28null CD8+ T and NKT-like cells in COPD. There was a significant negative correlation between HDAC2 expression and the percentage of CD28null CD8+ T and NKT-like cells producing IFNγ or TNFα in all subjects (eg, COPD: R = −.763, p < 0.001 for T-cell IFNγ). There was a synergistic upregulation of HDAC2 and associated decrease in pro-inflammatory cytokine production in CD28nullCD8+ T and NKT-like cells in the presence of 5 mg/L theophylline + 10−6 M prednisolone or 2.5 ng/mL cyclosporine A (CsA).ConclusionsLymphocyte senescence in COPD is associated with loss of HDAC2 in CD28nullCD8+ T and NKT-like cells. Alternative treatment options such as combined theophylline with low-dose CsA, that inhibit these pro-inflammatory cells, may reduce systemic inflammation in COPD.
Highlights
Histone acetyltransferases (HAT) and histone deacetylases (HDAC) are enzymes that upregulate and down-regulate pro-inflammatory gene transcription respectively
Increased CD28null CD8+ T and NKT-like cells in Chronic obstructive pulmonary disease (COPD) patients There was a significant increase in CD28nullCD8+ T cells in patients with COPD compared with healthy controls, but no change in CD28nullCD8− T cells (CD28nullCD8+ T: 57 ± 8.4 (33 ± 8.5); CD28nullCD8− T: 7.1 ± 3.1 (5.9 ± 4.2) for COPD patients consistent
HDAC2 and HAT expression by CD28+ and CD28null T and NKT-like cells A significantly lower percentage of CD28nullCD8+ T and NKT-like cells expressing HDAC2 in both COPD groups and controls was found, compared with CD28+ T and NKT-like cells (Data for T cell and NKT-like cell subsets from COPD group shown in Fig. 1)
Summary
Histone acetyltransferases (HAT) and histone deacetylases (HDAC) are enzymes that upregulate and down-regulate pro-inflammatory gene transcription respectively. We have shown that COPD patients have increased steroid resistant CD28null (senescent) pro-inflammatory T and NKT-like peripheral blood cells ( CD8+ subsets) and we hypothesized that these changes would be associated with a loss of HDAC2 from these senescent pro-inflammatory lymphocytes. Chronic obstructive pulmonary disease (COPD) is a leading cause of death world wide and existing treatments, such as anti-inflammatory corticosteroids, have no proven disease modifying effect [1] The mechanisms underlying this resistance are largely unknown, in lymphocytes [2]. We have shown that COPD is associated with increased CD28nullCD8+ senescent cells in the peripheral blood of both current and exsmoker COPD subjects, and showed these cells are more cytotoxic/pro-inflammatory than CD8 + CD28+ cells [5]. CD8 + CD28null NKT-like cells have been shown to be more pro-inflammatory and cytotoxic than CD8 + CD28+ NKTlike cells in other pro-inflammatory lung diseases [8]
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