The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase

Matt Randall, G.R. Haenen, F.G. Bouwman, A.V. Vliet, A. Bast

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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 0.5h 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 TNFalpha gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFalpha 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.
Original languageEnglish
Pages (from-to)43-49
Number of pages7
JournalToxicology Letters
Volume240
Issue number1
Early online date1 Jan 2015
DOIs
Publication statusPublished - 5 Jan 2016

Keywords

  • COPD
  • HDAC
  • Acrolein
  • Glucocorticoid
  • Inflammation
  • OBSTRUCTIVE PULMONARY-DISEASE
  • INFLAMMATORY CYTOKINE PRODUCTION
  • CIGARETTE-SMOKE
  • ALPHA,BETA-UNSATURATED ALDEHYDES
  • AIRWAY INFLAMMATION
  • HUMAN MACROPHAGES
  • EPITHELIAL-CELLS
  • PROTEIN
  • ALKYLATION
  • RECEPTOR

Cite this

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title = "The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase",
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 0.5h 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 TNFalpha gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFalpha 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.",
keywords = "COPD, HDAC, Acrolein, Glucocorticoid, Inflammation, OBSTRUCTIVE PULMONARY-DISEASE, INFLAMMATORY CYTOKINE PRODUCTION, CIGARETTE-SMOKE, ALPHA,BETA-UNSATURATED ALDEHYDES, AIRWAY INFLAMMATION, HUMAN MACROPHAGES, EPITHELIAL-CELLS, PROTEIN, ALKYLATION, RECEPTOR",
author = "Matt Randall and G.R. Haenen and F.G. Bouwman and A.V. Vliet and A. Bast",
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language = "English",
volume = "240",
pages = "43--49",
journal = "Toxicology Letters",
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The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase. / Randall, Matt; Haenen, G.R.; Bouwman, F.G.; Vliet, A.V.; Bast, A.

In: Toxicology Letters, Vol. 240, No. 1, 05.01.2016, p. 43-49.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase

AU - Randall, Matt

AU - Haenen, G.R.

AU - Bouwman, F.G.

AU - Vliet, A.V.

AU - Bast, A.

PY - 2016/1/5

Y1 - 2016/1/5

N2 - 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 TNFalpha gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFalpha 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.

AB - 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 TNFalpha gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFalpha 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.

KW - COPD

KW - HDAC

KW - Acrolein

KW - Glucocorticoid

KW - Inflammation

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - INFLAMMATORY CYTOKINE PRODUCTION

KW - CIGARETTE-SMOKE

KW - ALPHA,BETA-UNSATURATED ALDEHYDES

KW - AIRWAY INFLAMMATION

KW - HUMAN MACROPHAGES

KW - EPITHELIAL-CELLS

KW - PROTEIN

KW - ALKYLATION

KW - RECEPTOR

U2 - 10.1016/j.toxlet.2015.10.009

DO - 10.1016/j.toxlet.2015.10.009

M3 - Article

VL - 240

SP - 43

EP - 49

JO - Toxicology Letters

JF - Toxicology Letters

SN - 0378-4274

IS - 1

ER -