Wood Smoke Enhances Cigarette Smoke–Induced Inflammation by Inducing the Aryl Hydrocarbon Receptor Repressor in Airway Epithelial Cells

Abstract

Our previous studies showed that cigarette smokers who are exposed to wood smoke (WS) are at an increased risk for chronic bronchitis and reduced lung function. The present study was undertaken to determine the mechanisms for WS-induced adverse effects. We studied the effect of WS exposure using four cohorts of mice. C57Bl/6 mice were exposed for 4 or 12 weeks to filtered air, to 10 mg/m 3 WS for 2 h/d, to 250 mg/m 3 cigarette smoke (CS) for 6 h/d, or to CS followed by WS (CW). Inflammation was absent in the filtered air and WS groups, but enhanced by twofold in the bronchoalveolar lavage of the CW compared with CS group as measured by neutrophil numbers and levels of the neutrophil chemoattractant, keratinocytederived chemokine. The levels of the anti-inflammatory lipoxin, lipoxin A4, were reduced by threefold along with cyclo-oxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in airway epithelial cells and PGE 2 levels in the bronchoalveolar lavage of CW compared with CS mice. We replicated, in primary human airway epithelial cells, the changes observed in mice. Immunoprecipitations showed that WS blocked the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transporter to reduce expression of COX-2 and mPGES-1 by increasing expression of AHR repressor (AHRR). Collectively, these studies show that exposure to low concentrations of WS enhanced CS-induced inflammation by inducing AHRR expression to suppress AHR, COX-2, and mPGES-1 expression, and levels of PGE 2 and lipoxin A4. Therefore, AHRR is a potential therapeutic target for WS-associated exacerbations of CS-induced inflammation.

DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations With Cigarette Smoking and Subclinical Atherosclerosis

“…Previous studies indicate that AHRR is transcriptionally up-regulated by activation of the Ah Receptor pathway 12, 13 . Interestingly, RRBS showed that the AHRR cg05575921 locus is located in a smoking-associated DMR, which appears to overlap an intragenic enhancer that is activated, accompanied by up-regulation of AHRR expression, when monocytes differentiate into macrophages 19 .…”

“…The consequences of AHRR up-regulation in monocytes is unclear, but given the potential role of AHRR in macrophage biology 19 and suppression of anti-inflammation 13 , up-regulation of AHRR could plausibly alter the function of monocytes and macrophages in smokers. While there is currently no known role for AHRR in atherogenesis, a number of studies have shown that activation of the Ah Receptor pathway promotes atherosclerosis.…”

“…Previous studies indicate that AHRR, a basic helix–loop–helix/Per-ARNT-Sim (bHLH/PAS) family transcription factor, is transcriptionally regulated through activation of the Ah Receptor (AhR) pathway 12, 13 . Tobacco smoke contains numerous agonists of AhR signaling 14 and persistent activation of the AhR signaling pathway has been hypothesized to contribute to atherogenesis 15–18 .…”

“…Tobacco smoke contains numerous agonists of AhR signaling 14 and persistent activation of the AhR signaling pathway has been hypothesized to contribute to atherogenesis 15–18 . While there is currently no known role for AHRR in atherogenesis, recent studies implicate up-regulation of AHRR expression in monocyte-to-macrophage differentiation 19 and suppression of anti-inflammation 13 . We hypothesized that altered AHRR methylation levels in CD14+ monocytes, a cell type sensitive to cigarette smoking 20 and involved in atherogenesis 21, 22 , might provide a biological link between smoking and atherosclerotic plaque formation.…”

Study of the impact of smoking as a risk factor for atherosclerosis on the level of DNA methylation

“…Благодаря исследованиям ассоциаций эпигенома (EWAS -Epigenome-wide Association Studies) уже выявле-но большое количество CpG сайтов (CpG) в различных генах, метилирование которых связано с курением [15][16][17][18][19][20][21][22][23][24][25][26][27]. Все они вовлечены в разнообразные клеточные про-цессы, например AHRR и CYP1A1 участвуют в сигнальном ПРОФИЛАКТИЧЕСКАЯ МЕДИЦИНА, 6,2015 Сведения об авторах: Киселева Анна Витальевна -к.б.н., н.с.…”