The aryl hydrocarbon receptor suppresses cigarette-smoke-induced oxidative stress in association with dioxin response element (DRE)-independent regulation of sulfiredoxin 1

Sarill, Miles; Zago, Michela; Sheridan, Jared A.; Nair, Parameswaran; Matthews, Jason; Gomez, Alvaro; Roussel, Lucie; Rousseau, Stéphane; Hamid, Qutayba; Eidelman, David H.; Baglole, Carolyn J.

doi:10.1016/j.freeradbiomed.2015.08.007

Cited by 37 publications

(52 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we and others have shown that the potential biological function of the AhR extends well-beyond its transcriptional response to man-made toxicants; these studies have implicated the AhR in the regulation of development, immune homeostasis, cell death and inflammation8121322303233. Our new data presented herein suggest that the AhR is involved in the regulation of pulmonary miRNA, a group of ncRNA that are now recognized as major regulators of protein expression.…”

Section: Discussionmentioning

confidence: 59%

See 1 more Smart Citation

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

Rogers

Souza

Zago

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for its toxic responses to man-made pollutants such as dioxin. More recently, the AhR has emerged as a suppressor of inflammation, oxidative stress and apoptosis from cigarette smoke by mechanisms that may involve the regulation of microRNA. However, little is known about the AhR regulation of miRNA expression in the lung in response to inhaled toxicants. Therefore, we exposed Ahr−/− and Ahr+/− mice to cigarette smoke for 4 weeks and evaluated lung miRNA expression by PCR array. There was a dramatic regulation of lung miRNA by the AhR in the absence of exogenous ligand. In response to cigarette smoke, there were more up-regulated miRNA in Ahr−/− mice compared to Ahr+/− mice, including the cancer-associated miRNA miR-96. There was no significant change in the expression of the AhR regulated proteins HuR and cyclooxygenase-2 (COX-2). There were significant increases in the anti-oxidant gene sulfiredoxin 1 (Srxn1) and FOXO3a- predicted targets of miR-96. Collectively, these data support a prominent role for the AhR in regulating lung miRNA expression. Further studies to elucidate a role for these miRNA may further uncover novel biological function for the AhR in respiratory health and disease.

show abstract

Section: Discussionmentioning

confidence: 59%

“…We were the first to show in vitro that the AhR promotes the induction of Srxn1 expression by a mechanism that is independent of DRE binding30. Srxn1 is an endogenous antioxidant that protects against cigarette smoke-induced oxidative stress31.…”

Section: Resultsmentioning

confidence: 99%

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

Rogers

Souza

Zago

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…AhR −/− mice are more susceptible to colon carcinogenesis, inflammation, and hyperoxic lung injury [84] (for review, see [95]). Lung fibroblasts gained from patients suffering from chronic obstructive pulmonary disease (COPD) express less AhR protein than patients without COPD and show decreased upregulation of NQO1 and Srxn in response to cigarette smoke extract [58]. Low expression of the AhR is also found in inflammatory bowel disease [96].…”

Section: Discussionmentioning

confidence: 99%

“…The authors later showed that the promoter of SOD1 also contains a functional ARE and that TCDD-dependent activation of SOD1 requires both regulatory elements, that is, XRE and ARE [56]. Interestingly, basal expression of SOD1 (and SOD2) was diminished in primary lung fibroblasts derived from AhR −/− -mice, but expression of SOD1 could not be increased by cigarette smoke extract in wt-fibroblasts [57, 58]. Very recently, it was demonstrated that fetal pulmonary cells derived from AhR −/− -mice displayed reduced SOD1 induction in response to hyperoxia [59].…”

Section: Expression Of Superoxide Dismutasementioning

confidence: 99%

“…Cigarette smoke extract-mediated Srxn induction was significantly reduced in AhR −/− fibroblasts. Interestingly, cigarette smoke extract induced similar induction of Srxn mRNA in fibroblasts derived from AhR DBD/DBD -mice, which carry an AhR mutant unable to bind to XREs [77], compared to wt-mice [58]. This indicates that Srxn upregulation, in response to cigarette smoke extract, does not involve the classical AhR-XRE pathway but rather is mediated by a noncanonical AhR-dependent mechanism.…”

Section: Upregulation Of Sulfiredoxinmentioning

confidence: 99%

See 1 more Smart Citation

Antioxidant Functions of the Aryl Hydrocarbon Receptor

Dietrich

2016

Stem Cells International

119

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT) and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

show abstract