Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes.
BACKGROUND
Histone 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.


METHODS
Blood 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.


RESULTS
There 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).


CONCLUSIONS
Lymphocyte 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.
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. greg.hodge@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. greg.hodge@health.sa.gov.au.
Greg
G
Hodge
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. hubertus.jersmann@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. hubertus.jersmann@health.sa.gov.au.
Hubertus
H
Jersmann
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. hai.tran@health.sa.gov.au.
Hai B
HB
Tran
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. eugene.roscioli@health.sa.gov.au.
Eugene
E
Roscioli
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. mark.holmes@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. mark.holmes@health.sa.gov.au.
Mark
M
Holmes
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. paul.reynolds@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. paul.reynolds@health.sa.gov.au.
Paul N
PN
Reynolds
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia. sandra.hodge@health.sa.gov.au.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia. sandra.hodge@health.sa.gov.au.
Sandra
S
Hodge
D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D016022:Case-Control Studies; D016922:Cellular Senescence / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D051548:Histone Acetyltransferases / Q000097:blood; D056464:Histone Deacetylase 2 / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000201:enzymology / Q000276:immunology; D010641:Phenotype; D011239:Prednisolone / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000276:immunology; D013806:Theophylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D018106:CD28 Antigens; D020536:Enzyme Activators; C573415:IFNG protein, human; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016572:Cyclosporine; D011239:Prednisolone; D013806:Theophylline; D051548:Histone Acetyltransferases; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2