The online version of this article (doi:10.1186/s12890-015-0155-3) contains supplementary material, which is available to authorized users.
None of the authors has a competing interest.
BGC: designed the protocol, acquired data, analyzed data and prepared manuscript, AJ: performed the experiments on cell lines, AI: performed the experiments on alveolar macrophages, HS: analyzed data and prepared the manuscript, XB: designed the protocol and performed the molecular assays, AA: data analysis and manuscript preparation. All authors read and approved the final version of the manuscript.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before.
The effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-κB) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 μM) and/or the HDAC enhancer theophylline (10 μM).
Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-κB and induced the secretion of several cytokines (IL-6, IL-8, IL-1β, IL-10 and TNF-α) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-κB activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-κB activation.
These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-κB mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity.
Additional file 1: Figure S1. Effect of H. influenza infection on inflammatory cytokines release from alveolar macrophages obtained from COPD patients, smoker and non-smoker controls. Abbreviations NTHi: Nontypeable Haemophilus influenzae (*p < 0.05 over control cells). Figure S2. Effect of Dexamethasone and Theophylline on cytokine release in co-culture cells after Haemophilus influenzae infection. Abbreviations Dex: dexamethasone 1 μM, Theo: theophylline 10 μM, NTHi: Nontypeable Haemophilus influenzae (*p < 0.05 over infected cells with NTHi). (PDF 18 kb)12890_2015_155_MOESM1_ESM.pdf
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- Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD
Borja G. Cosío
- BioMed Central
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