The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase.
Chronic obstructive pulmonary disease (COPD) is the leading cause of cigarette smoke-related death worldwide. Acrolein, a crucial reactive electrophile found in cigarette smoke mimics many of the toxic effects of cigarette smoke-exposure in the lung. In macrophages, cigarette smoke is known to hinder histone deacetylases (HDACs), glucocorticoid-regulated enzymes that play an important role in the pathogenesis of glucocorticoid resistant inflammation, a common feature of COPD. Thus, we hypothesize that acrolein plays a role in COPD-associated glucocorticoid resistance. To examine the role of acrolein on glucocorticoid resistance, U937 monocytes, differentiated with PMA to macrophage-like cells were treated with acrolein for 0.5h followed by stimulation with hydrocortisone for 8h, or treated simultaneously with LPS and hydrocortisone for 8h without acrolein. GSH and nuclear HDAC activity were measured, or gene expression was analyzed by qPCR. Acrolein-mediated TNFα gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFα expression was suppressed. Acrolein also significantly inhibited nuclear HDAC activity in macrophage-like cells. Incubation of recombinant HDAC2 with acrolein led to the formation of an HDAC2-acrolein adduct identified by mass spectrometry. Therefore, these results suggest that acrolein-induced inflammatory gene expression is resistant to suppression by the endogenous glucocorticoid, hydrocortisone.
Department of Toxicology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands; Department of Pathology, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: mjrandal@uvm.edu.
Matthew J
MJ
Randall
Department of Toxicology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Guido R M M
GR
Haenen
Department of Human Biology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Freek G
FG
Bouwman
Department of Pathology, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
Albert
A
van der Vliet
Department of Toxicology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Aalt
A
Bast
D000171:Acrolein / Q000633:toxicity*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004351:Drug Resistance; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D005938:Glucocorticoids; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000171:Acrolein; D056464:Histone Deacetylase 2; D005978:Glutathione; D006854:Hydrocortisone
Acrolein; COPD; Glucocorticoid; HDAC; Inflammation