The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase. Issue 1 (5th January 2016)

• Record Type: Journal Article
• Authors: Randall, Matthew J.; Haenen, Guido R.M.M.; Bouwman, Freek G.; Vliet, Albert van der; Bast, Aalt
• Is Part Of: Toxicology letters. Volume 240:Issue 1(2016)
• Page Start: 43
• Page End: 49
• Publication Date: 2016-01-05
• Subjects: COPD chronic obstructive pulmonary disease -- HDAC histone deacetylase -- PMA phorbol 12-myristate 13-acetate -- LPS lipopolysaccharide -- GSH glutathione -- qPCR quantitative polymerase chain reaction -- TNFα tumor necrosis factor α -- 4-HNE 4-hydroxynonenal -- IL-8 interleukin 8 -- Cys cysteine -- FBS fetal bovine serum -- RPMI Roswell Park Memorial Institute media -- HBSS Hanks balanced salt solution -- SSA sulfosalicylic acid -- DTNB Ellman's reagent -- MALDI-TOF Matrix-assisted laser desorption/ionization-time of flight; COPD -- HDAC -- Acrolein -- Glucocorticoid -- Inflammation; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2015.10.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Acrolein-mediated pro-inflammatory gene expression is resistant to hydrocortisone. Acrolein treatment of macrophage-like cells decreases nuclear HDAC acitivity. Cysteine 274 on HDAC2 is a target for acrolein adduction. Abstract: 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 0.5 h followed by stimulation with hydrocortisone for 8 h, or treated simultaneously with LPS and hydrocortisone for 8 h 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.