Journal
PULMONARY PHARMACOLOGY & THERAPEUTICS
Volume 25, Issue 4, Pages 286-292Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pupt.2012.05.003
Keywords
COPD; Cigarette smoke; Macrophages; Histone deacetylase; Cytokines
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Chronic obstructive pulmonary disease (COPD) is a debilitating condition resulting from exposure to pollutants such as cigarette smoke. Pulmonary macrophages secrete a plethora of inflammatory mediators that are increased in the lungs of COPD patients, but whether this phenotype results directly from smoke exposure remains unknown. Using an in vitro model for alveolar macrophages (AM) derived from human peripheral blood monocytes with granulocyte-macrophage stimulating factor (GM-Mempty set), we analyzed the mechanistic connection between cigarette smoke exposure and histone deacetylase (HDAC) regulation, hypothesized to be a contributing factor in COPD pathophysiology. Here we show that acute smoke exposure inhibits HDAC enzymatic activity in GM-Mempty set. Analysis of mRNA and total cellular proteins for expression of class I (1, 2, 3 and 8), class 11 (4, 5, 6, 7, 9, 10), and class IV (11) HDAC revealed no effect of smoke exposure, whereas nuclear HDAC3 protein content was reduced. To better understand the physiological significance of reduced HDAC3 activity, we utilized siRNA to knockdown HDAC1, 2 and 3 individually. Interestingly, siRNA-mediated reduction of HDAC3 resulted in increased production of IL8 and IL1 beta in response to LPS stimulation, while HDAC2 knockdown had no effect on either cytokine. Lower nuclear content of HDAC3 in the context of equivalent total HDAC protein levels following smoke exposure may reflect increased nuclear export of HDAC3, allowing increased nuclear factor kappa b (NF-kappa B) driven cytokine expression that can contribute to inflammation. (C) 2012 Elsevier Ltd. All rights reserved.
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