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Free Radic Biol Med. 2017 Jul;108:19-31. doi: 10.1016/j.freeradbiomed.2017.02.045. Epub 2017 Feb 27.

RelB attenuates cigarette smoke extract-induced apoptosis in association with transcriptional regulation of the aryl hydrocarbon receptor.

Author information

1
Department of Medicine, McGill University, Montreal, Quebec, Canada.
2
Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
3
Department of Physiology, McGill University, Montreal, Quebec, Canada.
4
Department of Pathology, McGill University, Montreal, Quebec, Canada.
5
Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada.
6
Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
7
Department of Medicine, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
8
Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montreal, Quebec, Canada; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada. Electronic address: Carolyn.baglole@McGill.ca.

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic and prevalent respiratory disease caused primarily by long term inhalation of cigarette smoke. A major hallmark of COPD is elevated apoptosis of structural lung cells including fibroblasts. The NF-κB member RelB may suppress apoptosis in response to cigarette smoke, but its role in lung cell survival is not known. RelB may act as a pro-survival factor by controlling the expression of superoxide dismutase 2 (SOD2). SOD2 is also regulated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that suppresses cigarette smoke-induced apoptosis. As the AhR is also a binding partner for RelB, we speculate that RelB suppresses cigarette smoke-induced apoptosis by regulating the AhR. Using an in vitro model of cigarette smoke exposure (cigarette smoke extract [CSE]), we found that CSE down-regulated RelB expression in mouse lung fibroblasts, which was associated with elevated levels of cleaved PARP. Genetic ablation of RelB elevated CSE-induced apoptosis, including chromatin condensation, and reduced mitochondrial function. There was also more reactive oxygen species production in RelB-/- cells exposed to CSE. While there was no alteration in Nrf2 expression or localization between RelB-/- and wild type cells in response to CSE, RelB-/- cells displayed significantly decreased AhR mRNA and protein expression, concomitant with loss of AhR target gene expression (Cyp1a1, Cyp1b1, Nqo1). Finally, we found that RelB binds to the Ahr gene at 3 sites to potentially increase its expression via transcriptional induction. These data support that RelB suppresses cigarette smoke-induced apoptosis, potentially by increasing the AhR. Together, these two proteins may comprise an important cell survival signaling pathway that reduces apoptosis upon cigarette smoke exposure.

KEYWORDS:

Apoptosis; Chromatin immunoprecipitation (ChiP); Chronic obstructive pulmonary disease (COPD); Cigarette smoke

[Indexed for MEDLINE]

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